(4-piperidinylmethyl and -hetero) purines

ABSTRACT

(4-Piperidinylmethyl and -hetero)purines having antihistaminic properties and being useful agents in the treatment of allergic diseases.

This is a continuation of application Ser. No. 858,339, filed May 1,1986, now abandoned.

BACKGROUND OF THE INVENTION

In U.S. Pat. No. 4,219,559 there are described a number ofN-heterocyclyl-4-piperidinamines having antihistaminic properties.

In European Patent Publication Nos. 0,999,139; 0,145,037 and 0,144,101there are also described a number of N-heterocyclyl-4-piperidinamines ascompounds having antihistaminic and serotoninantagonistic properties.

The compounds of the present invention differ from the prior artcompounds essentially by the nature of the 4-piperidinyl substituentwhich is invariably a purinylmethyl or -hetero group.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

This invention is concerned with novel (4-piperidinylmethyl and-hetero)purines which may structurally be represented by the formula##STR1## the pharmaceutically acceptable acid addition salts and thepossible stereochemically isomeric forms thereof, wherein:

--A¹ ═A² --A³ ═A⁴ -- is a bivalent radical having the formula

    --N═CH--N═CH--                                     (a-1),

or

    --CH═N--CH═N--                                     (a-2),

wherein one or two hydrogen atoms in said radicals (a-1) or (a-2) may,each independently from each other, be replaced by halo, C₁₋₆ alkyl,C₁₋₆ alkyloxy, trifluoromethyl or hydroxy;

R¹ is a member selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₆ cycloalkyl, Ar¹ and C₁₋₆ alkyl substituted with one or twoAr¹ radicals;

R² is a member selected from the group consisting of hydrogen and C₁₋₆alkyl;

B is CH₂, NR, O, S, SO or SO₂ ; said R being a member selected from thegroup consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, (C₁₋₆alkyl)--CO--, (C₁₋₆ alkyloxy)--CO and Ar² --C₁₋₆ alkyl;

L is a member selected from the group consisting of a radical of formula

    L.sup.1 --C.sub.r H.sub.2r --T--C.sub.s H.sub.2s --        (b-1);

and a radical of formula ##STR2## wherein one or two hydrogen atoms inthe bivalent radical --C_(s) H_(2s) -- may, each independently from eachother, be replaced by halo, hydroxy, mercapto, isothiocyanato,isocyanato, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, Ar¹, Ar¹ O--, Ar¹ S--, Ar¹SO₂ --, or NHR³ R⁵ ; and

n is 0 or the integer 1 or 2;

r and s, are independently from each other, 0 or an integer of from 1 to6 inclusive;

T is --Y-- or ##STR3## T¹ is ##STR4## or a direct bond; said Y being O,S, NR or a direct bond;

X being O, S, CH--NO₂ or NR⁴ ;

Z being O, S, NR⁵ or a direct bond; and

said R³ being hydrogen, C₁₋₆ alkyl, Ar² --C₁₋₆ alkyl, 2-(C₁₋₆alkyloxy)-1,2-dioxoethyl or a radical of formula --C(═X)--R⁶, R⁶ beinghydrogen, C₁₋₆ alkyl, Ar², Ar² --C₁₋₆ alkyl, C₁₋₆ alkyloxy, Ar² --C₁₋₆alkyloxy, mono- or di(C₁₋₆ alkyl)amino, Ar² -amino, Ar² --C₁₋₆alkylamino or Ar² --C₁₋₆ alkyl(C₁₋₆ alkyl)amino;

said R⁴ being hydrogen, C₁₋₆ alkyl, cyano, nitro, Ar² -sulfonyl, C₁₋₆alkylsulfonyl, C₁₋₆ alkylcarbonyl or Ar² -carbonyl; and

said R⁵ being hydrogen or C₁₋₆ alkyl;

wherein L¹ is a member selected from the group consisting of hydrogen;halo; hydroxy; C₁₋₆ alkyloxy; C₁₋₆ alkylthio; cyano; mercapto;isocyanato; isothiocyanato; Ar¹ ; Ar¹ -carbonyl; Ar¹ -sulfonyl; C₁₋₆alkylsulfonyl; C₃₋₆ cycloalkyl being optionally substituted with up totwo substituents each independently selected from the group consistingof C₁₋₆ alkyl, cyano and Ar² ;[10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]methyl; Het; andfuran substituted with substituted C₁₋₆ alkyl; said substituted C₁₋₆alkyl being C₁₋₆ alkyl substituted with a member selected from the groupconsisting of hydroxy, mercapto, C₁₋₆ alkyloxy, C₁₋₆ alkylthio,aminoC₁₋₆ alkylthio, Ar² -oxy and a radical of formula ##STR5## wherein:t is 0 or an integer of from 1 to 6 inclusive; and R⁷ is hydrogen orC₁₋₆ alkyl; provided that: when in said radical of formula (c) t is 0,then Z or Y is a direct bond; and

where r is 0, L¹ may also be C₂₋₆ alkenyl, Ar¹ --C₂₋₆ alkenyl or C₁₋₆alkyl substituted with two C₁₋₆ alkyloxy radicals; and

where r is 0 and T is NR³, or T is --N(R⁵)--C(═X)--Y or T¹ is--N(R⁵)--C(═X)--, L¹ may also be amino, C₁₋₆ alkylamino or Ar¹ -amino;and

where r is 0, and R is --N(R⁵)--C(═X)--Y or T¹ is --N(R⁵)--C(═X)--, L¹may also be nitro;

said Het being an optionally substituted five- or six-memberedheterocyclic ring, being optionally condensed with an optionallysubstituted five- or six-membered carbocyclic or heterocyclic ring;

provided that:

i) when L is a radical of formula (b-1) wherein L¹ is hydrogen andwherein T is --Z--C(═X)--Y-- wherein Y is other than a direct bond and Zand X are each independently O or S, then r is not 0; or when L is aradical of formula (b-2) wherein L¹ is hydrogen and wherein T¹ is--Z--C(═X)-- wherein Z and X are each independently O or S, then r isnot 0;

ii) when L is a radical of formula (b-1) wherein L¹ is halo, hydroxy,C₁₋₆ alkyloxy, mercapto, C₁₋₆ alkylthio, isocyanato, isothiocyanato orHet connected to C_(r) H_(2r) on a nitrogen atom, and wherein r is 0,then T is a direct bond or a radical --C(═X)--Y--; or when L is aradical of formula (b-2) wherein L¹ is halo, hydroxy, C₁₋₆ alkyloxy,mercapto, C₁₋₆ alkylthio, isocyanato, isothiocyanato or Het connected toC_(r) H_(2r) on a nitrogen atom, and wherein r is 0, then T¹ is aradical --C(═X)--;

iii) when L is a radical of formula (b-1) wherein T is Y, said Y beingother than a direct bond, or wherein T is --Z--C(═X)--Y--, wherein Y isother than a direct bond, then s is not 0;

wherein Ar¹ is a member selected from the group consisting of phenyl,substituted phenyl, naphthalenyl, thienyl, halothienyl, C₁₋₆alkylthienyl, pyridinyl, mono- and di(C₁₋₆ alkyloxy)pyridinyl, pyrrolyl,C₁₋₆ alkylpyrrolyl, furanyl, furanyl substituted with C₁₋₆ alkyl,pyrazinyl, thiazolyl, imidazolyl, C₁₋₆ alkylimidazolyl; said substitutedphenyl, being phenyl substituted with up to 3 substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino, C₁₋₆alkylsulfonyl, C₁₋₆ alkylsulfonylC₁₋₆ alkyl, phenylC₁₋₆ alkylsulfonyl,phenylsulfonylC₁₋₆ alkyl, a radical of formula R⁸ --C_(p) H_(2p) --Y--,a radical of formula R⁹ --Z--C(═X)--Y--, and a radical of formula R¹⁰SO₂ Y--; wherein p is an integer of from 1 to 6 inclusive and R⁸ is amember selected from the group consisting of amino, cyano, phenylaminocarbonyl, mono- and di(C₁₋₆ alkyl)aminocarbonyl, C₁₋₆alkyloxycarbonyl, phenylC₁₋₆ alkyloxycarbonyl, 4-morpholinylcarbonyl,1-piperidinylcarbonyl, 1-pyrrolidinylcarbonyl, and C₂₋₆ alkenyl; whereinR⁹ is member selected from the group consisting of hydrogen, C₁₋₆ alkyland Ar² ; provided that, when R⁹ is hydrogen and Y is other than adirect bond, then Z is not O or S; and wherein R¹⁰ is C₁₋₆ alkyl or Ar²;

wherein Ar² is a member selected from the group consisting of phenyl,substituted phenyl, thienyl and furanyl, said substituted phenyl beingphenyl optionally substituted with up to three substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino, carboxyl,C₁₋₆ alkyloxycarbonyl and (C₁₋₆ alkyl)--CO.

As used in the foregoing definitions the term halo is generic to fluoro,chloro, bromo and iodo; the term "C₁₋₆ alkyl" is meant to includestraight and branch chained saturated hydrocarbon radicals having from 1to 6 carbon atoms such as, for example, methyl, ethyl, 1-methylethyl,1,1-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and thelike; "C₁₋₁₀ alkyl" is meant to include C₁₋₆ alkyl radicals, as definedhereinabove, and the higher homologs thereof having from 7 to 10 carbonatoms; the term "C₂₋₆ alkenyl" is meant to include straight and branchchained hydrocarbon radicals having from 2 to 6 carbon atoms, such as,for example, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and the like;the term "C₃₋₆ cycloalkyl" is generic to cyclopropyl, cyclobutyl,cyclopentyl and cyclohexyl; and "C₁₋₆ alkanediyl" is meant to includebivalent straight or branch chained alkanediyl radicals having from 1 to6 carbon atoms.

Preferred compounds within the invention are those wherein Het is afive- or six-membered heterocyclic ring containing a number ofheteroatoms which varies of from 1 to 4, said heteroatoms being selectedfrom the group consisting of oxygen, sulfur and nitrogen, provided thatno more than two oxygens or sulfurs are present, said five orsix-membered ring being optionally condensed with a five- orsix-membered carbocyclic or heterocyclic ring also containing a numberof heteroatoms which varies from 1 to 4, the latter heteroatoms beingselected from the group consisting of oxygen, sulfur and nitrogen,provided that no more than 2 oxygens or sulfurs are present, and whereinsaid Het being a bicyclic ring system may optionally be substituted withup to 6 substituents, or said Het being a monocyclic ring system mayoptionally be substituted with up to 3 substituents, said substituentsof Het being selected from the group consisting of a bivalent radical offormula ═X, said ═X independently having the same meaning of thepreviously defined X; halo; isocyanato; isothiocyanato; nitro, cyano,trifluoromethyl; a radical of formula A-Y-, wherein A is hydrogen, Ar¹or C₁₋₆ alkyl being optionally substituted with Ar¹, C₁₋₆ alkyloxy, Ar¹O, hydroxy, C₁₋₆ alkyloxycarbonyl and Y independently has the samemeaning of the previously defined Y; and a radical A--Z--C(═X)--Y--,wherein A is as defined hereinabove and Z, X and Y independently havethe same meanings of the previously defined Z, X and Y; provided that(i) when in the radical A-Y-A is hydrogen, then Y is other than a directbond, or (ii) when in the radical A--Z--C(═X)--Y--A is hydrogen and Y isNR³, O or S, then Z is other than O or S.

Particularly preferred compounds within the invention are those whereinHet is a member selected from the group consisting of

i) pyridinyl which is optionally substituted with one or twosubstituents each independently selected from the group consisting ofhalo, amino, mono- and diC₁₋₆ alkyl amino, Ar² C₁₋₆ alkylamino, nitro,cyano, aminocarbonyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆alkyloxycarbonyl, hydroxy, C₁₋₆ alkylcarbonyloxy, Ar² --C₁₋₆ alkyl andcarboxyl; pyridinyloxide optionally substituted with nitro; quinolinylwhich is optionally substituted with C₁₋₆ alkyl; pyrimidinyl which isoptionally substituted with one or two substituents each independentlyselected from the group consisting of halo, amino, hydroxy, C₁₋₆ alkyl,C₁₋₆ alkyloxy, C₁₋₆ alkylthio and Ar² --C₁₋₆ alkyl; quinazolinyl whichis optionally substituted with hydroxy or C₁₋₆ alkyl; pyridazinyl whichis optionally substituted with C₁₋₆ alkyl or halo; quinoxalinyl which isoptionally substituted with C₁₋₆ alkyl; pyrazinyl which is optionallysubstituted with halo, amino or C₁₋₆ alkyl; phthalazinyl which isoptionally substituted with halo; morfolinyl; thiomorfolinyl;piperidinyl; 2,3-dihydro-3-oxo-4H-benzoxazinyl and2,3-dihydro-1,4-benzodioxinyl, both being optionally substituted withC₁₋₆ alkyl or halo; dioxanyl being optionally substituted with C₁₋₆alkyl; 2-oxo-2H-1-benzopyranyl and 4-oxo-4H-1-benzopyranyl both beingoptionally substituted with C₁₋₆ alkyl;1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl being optionally substitutedwith C₁₋₆ alkyl; and 4-oxo-2(1H)-pyrimidinyl;

5,6-dihydro-4H-1,3-thiazin-2-yl, thiazolyl, 4,5-dihydrothiazolyl,oxazolyl, imidazolyl, tetrazolyl, 1,3,4-thiadiazolyl, benzimidazolyl,benzothiazolyl, benzoxazolyl, 4,5-dihydro-5-oxo-1H-tetrazolyl,2-oxo-3-oxazolidinyl and indolyl whereby each of the Het-radicals ofgroup ii) may optionally be substituted where possible with up to twosubstituents selected from the group consisting of C₁₋₆ alkyl, Ar¹, Ar¹--C₁₋₆ alkyl, benzimidazolylC₁₋₆ alkyl, amino, (aminoiminomethyl)amino,mono- and di(C₁₋₆ alkyl)amino, Ar¹ -amino, nitro, C₁₋₆ alkyloxycarbonyland pyrimidinyl;

iii) a radical of formula ##STR6## wherein each X² is independently O orS; R¹¹, R¹², R¹⁴, R²² and R²⁴ are each independently hydrogen, C₁₋₆alkyl, Ar² --C₁₋₆ alkyl, hydroxyC₁₋₆ alkyl or C₁₋₆ alkyloxycarbonyl;R¹³, R¹⁶, R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹ and R²³ are each independentlyhydrogen, C₁₋₆ alkyl, hydroxy, mercapto, C₁₋₆ alkyloxy, C₁₋₆ alkylthio,halo and (C₁₋₆ alkyloxycarbonyl)C₁₋₆ alkyl; G¹ is --CH═CH--CH═CH--,--S--CH═CH-- or --N═CH--NH--; G² is --CH═CH--CH═CH--, --S--(CH₂)₂ --,--S--(CH₂)₃ --, --(CH₂)₄ -- or --S--CH═CH--; G³ is --CH═CH--CH═CH--,--CH₂ --NH--(CH₂)₂ --, --S--CH═CH--, --N═CH--CH═CH--, --CH═N--CH═CH-- ,--CH═CH--N═CH--, --CH═CH--CH--N--, --N═CH--CH--N--, --N═CH--N═CH-- or--CH═N--CH═N--; G⁴ is --CH₂ --NH--(CH₂)₂ --, --N═CH--CH═CH----CH═N--CH═CH--, --CH═CH--N═CH--, --CH═CH--CH--N--, --N═CH--N═CH-- or--CH═N--CH═N--; G⁵ is --N═CH--CH═CH--, --CH═N--CH═CH--, --CH═CH--N═CH--,--CH═CH--CH--N--, --N═CH--N═CH-- or --CH═N--CH═N--; G⁶ is--CH═CH--CH═CH--, --N═CH--CH═CH--, --CH═N--CH═CH--, --CH═CH--N═CH--,--CH═CH--CH--N--, --N═CH--N═CH-- or --CH═N--CH═N--;

wherein one or two hydrogen atoms in said radicals G¹, G², G³, G⁴, G⁵ orG⁶ or in the benzene part of the radicals of formula (e-2), (e-3) or(e-9) may be replaced by C₁₋₆ alkyl, C₁₋₆ alkylthio, C₁₋₆ alkyloxy orhalo where said hydrogen atom is bonded on a carbon atom, or by C₁₋₆alkyl, C₁₋₆ alkyloxycarbonyl, Ar² --C₁₋₆ alkyl, where said hydrogen isbonded on a nitrogen atom.

It is clear that R¹¹, R¹², R¹⁷, R¹⁸, R¹⁹, R²⁰, R²¹, R²² or R²³ is absentwhere the radical of formula (e-1), respectively (e-4), (e-5), (e-6) or(e-7) is connected to C_(s) H_(2s) on the atom bearing R¹¹, R¹², R¹⁷,R¹⁸, R¹⁹, R²⁰, R²¹, R²² or R²³.

More particularly preferred compounds within the invention are thosewherein L is a radical of formula (b-1).

Especially preferred compounds within the invention are those moreparticularly preferred compounds wherein Het is as described hereinabovefor the particularly preferred compounds, wherein r is 0 and L¹ ishydrogen, hydroxy, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, mercapto, Het, Ar¹,isocyanato, isothiocyanato or cyano.

More especially preferred compounds within the invention are thoseespecially preferred compounds wherein R¹ is C₁₋₆ alkyl substituted withone Ar¹ radical.

It is evident that in the compounds of formula (I) wherein L¹ is Het,said Jet may be unsaturated or partly or completely saturated.

The compounds of formula (I) wherein Het is a heterocycle which issubstituted with a hydroxy, mercapto or amino radical may contain intheir structure a keto-enol tautomeric system of a vinylog systemthereof, and consequently these compounds may be present in their ketoform as well as their enol form.

The compounds of formula (I) can generally be prepared by reacting apiperidine of formula (II) with a diamine of formula (III). ##STR7##

In some instances the reaction of (II) with (III) first yields anintermediate of formula ##STR8## which may in situ or, if desired, afterisolating and further purifying it, be cyclisized to the desiredcompounds of formula (I).

In (II) and (II-a) X¹ is O, S or NH.

W as used in the foregoing and following reaction schemes is anappropriate leaving group such as, for example, halo, e.g. chloro, bromoor iodo, a sulfonyloxy group, e.g. methylsulfonyloxy or4-methylphenylsulfonyloxy, and where W is connected to a --C(═X)--,--C(═X¹)-- or --C(═X²)-radical it may also be C₁₋₆ alkyloxy, C₁₋₆alkylthio, Ar² --O--, or Ar² --S--.

The piperidine of formula (II) may in situ be generated, for example, byconverting a piperidine which is substituted in its 4-position with a--B--C(═X¹)--OH radical into a piperidine of formula (II) by reactingthe former piperidine with thionyl chloride, phosphor trichloride,phosphoryl chloride, polyphosphoric acid, phosphoroxy chloride and thelike.

The reaction of (II) with (III) may be conducted in a suitable solventsuch as, for example, a hydrocarbon, e.g., benzene, hexane; an ether,e.g., 1,1'-oxybisethane, tetrahydrofuran; a ketone, e.g., 2-propanone,2-butanone; an alcohol, e.g., methanol, ethanol, 2-propanol, 1-butanol;a halogenated hydrocarbon, e.g., trichloromethane, dichloromethane, anorganic acid, e.g., acetic acid, propanoic acid; a polar aprotic solvente.g., N,N-dimethylformamide, N,N-dimethylacetamide and the like; andmixtures of such solvents. Depending upon the solvent and nature of W itmay be appropriate to add an appropriate base and/or a iodide salt,preferably an alkali metal iodide, to the reaction mixture. Elevatedtemperatures may enhance the reaction rate.

The compounds of formula (I) can also be prepared by reacting anintermediate of formula (V) with a piperidine of formula (IV) wherein E¹and E² are selected so that during the reaction a radical --B-- isformed. ##STR9##

For example, the compounds of formula (I) can be prepared by reacting apiperidine of formula (IV) wherein E¹ is a radical of formula --B--Mwith an intermediate of formula (V) wherein E² is a radical of formula--W. ##STR10##

In (IV-a) M is, depending upon the nature of B, hydrogen or anappropriate alkalimetal or earth alkaline metal and in (V-a) W has thepreviously described meaning. Additionally, the compounds of formula (I)can also be prepared by reacting a piperidine of formula (IV) wherein E¹is W with an intermediate of formula (V) wherein E² is a radical offormula --B--M, said W and M having the previously described meanings.##STR11##

More particularly, the compounds of formula (I) wherein B is --CH₂ --can also be prepared by reacting a piperidine of formula (IV) wherein E¹represents a radical of formula --CH₂ --W, (IV-c), with an intermediateof formula (V) wherein E² represents M, (V-c), or alternatively, byreacting a piperidine of formula IV, wherein E¹ is a radical of formula--M, (IV-d), with an intermediate of formula (v) wherein E² is a radicalof formula --CH₂ --W, (V-d). ##STR12##

The reaction of (IV) with (V) may conveniently be conducted in anappropriate solvent such as for example, an aromatic hydrocarbon, e.g.,benzene, methylbenzene; an ether, e.g. 1,4-dioxane, 1,1'-oxybisethane,tetrahydrofuran and the like; a halogenated hydrocarbon, e.g.trichloromethane and the like; N,N-dimethylformamide (DMF);N,N-dimethylacetamide (DMA); and where M is hydrogen, said solvent mayalso be a C₁₋₆ alkanol, e.g., methanol, ethanol, 1-butanol and the like;a ketone, e.g., 2-propanone, 4-methyl-2-pentanone and the like. In somecircumstances, the addition of an appropriate base such as, for example,an alkali metal carbonate or hydrogen carbonate, sodium hydride or anorganic base such as, for example, N,N-diethylethanamine orN-(1-methylethyl)-2-propanamine and/or the addition of a iodide salt,preferably an alkali metal iodide, may be appropriate. Somewhat elevatedtemperatures may enhance the rate of the reaction.

The compounds of formula (I), wherein B is NR, can also be prepared by acyclodesulfurization reaction of an appropriate thiourea derivative offormula ##STR13##

Said cyclodesulfurization reaction may be carried out by the reaction of(VI-a) with an appropriate alkyl halide, preferably iodomethane in anappropriate reaction-inert organic solvent, e.g. a C₁₋₆ alkanol such asmethanol, ethanol, 2-propanol and the like. Otherwise, thecyclodesulfurization reaction may be carried out by the reaction of(VI-a) with an appropriate metal oxide or salt in an appropriate solventaccording to art-known procedures. For example, the compounds of formula(I) can easily be prepared by the reaction of (VI-a) with an appropriateHg(II) or Pb(II) oxide or salt, such as, for example HgO, HgCl₂,Hg(OAc)₂, PbO or Pb(OAc)₂. In certain instances it may be appropriate tosupplement the reaction mixture with a small amount of sulfur. Even somethanediimines, especially N,N'-methanetetraylbis[cyclohexanamine] maybe used as cyclodesulfurizing agents.

In some instances compounds of formula (I), wherein B is NR, mayalternatively be prepared by cyclodesulfurizing a thiourea of formula(VI-b) and subsequently dehydrating the thus obtainedoxazole[5,4-d]pyrimidine derivatives with a suitable dehydrating agente.g., phosphoryl chloride, phosphor trichloride, phosphor pentachloride,thionyl chloride and the like. ##STR14##

In (VI-b) R^(1-a) has the same meaning as described hereinabove for R¹.

The compounds of formula (I) can also be converted into each other. Anumber of such reactions will be described hereinafter in more detail.

In order to simplify the structural representations of the compounds offormula (I) and of certain precursors and intermediates thereof the##STR15## represented by the symbol D.

The compounds of formula (I) wherein L is L², said compounds beingrepresented by the formula (I-b) can be prepared by alkylating anintermediate of formula (VII) with a compound of formula (I) wherein Lis Q², said compound being represented by the formula (I-c). ##STR16##L² as defined hereinabove is a radical of formula (b-1) other thanhydrogen, said radical being represented by the formula (b-1-a), or aradical of formula (b-2).

In (VII) and (I-c), Q¹ and Q² are selected so that a bivalent radical offormula (b-1-a) or (b-2) is formed during the alkylation reaction, said(b-1-a) and (b-2) having the previously described meaning.

For example, the compounds of formula (I-b) can be prepared byN-alkylating a piperidine of formula (I-c) wherein Q² is hydrogen, saidpiperidine being represented by the formula (I-c-1), with a reagent offormula (VII-a). ##STR17##

In some instances the alkylating reagent (VII-a) can also be a reactivecyclic reagent which may be formed by an intramolecular cyclisationreaction. The said cyclic form of (VII-a) may be formed in situ, or ifdesired, isolated and further purified before reacting it with (I-c-1).

Additionally, the compounds of formula (I-b), wherein L² is a radical offormula (b-1-a), wherein T is T², said T² being O, S, NR³ or --Z¹--C(═X)--Y--, said Z¹ being O, S or NR⁵, or a radical of formula (b-2)wherein T¹ is T³, said T³ being --Z¹ --C(═X)-- or a direct bond, saidcompounds being represented by the formulae (I-b-1-a), respectively(I-b-1-b), can be prepared by alkylating a piperidine of formula (I-c-2)with a reagent of formula (VII-b). ##STR18##

In (I-c-2) Q^(2a) is a radical of formula HT² --C_(s) H_(2s) --,respectively a radical of formula ##STR19## and W¹ has the previouslydefined meaning of W, and where r=0, and L¹ is Het or Ar¹, it may alsobe C₁₋₆ alkyloxy or C₁₋₆ alkylthio.

The compounds of formula (I-b), wherein L² is a radical of formula(b-1-a), wherein T is T⁴, said T⁴ being O, S, NR³ or --Z--C(═X)--Y¹ --,said Y¹ being O, S or NR³, and said compounds being represented by theformula (I-b-2), may also be prepared by alkylating a piperidine offormula (I-c) wherein Q² is a radical of formula --C_(s) H_(2s) --W,said piperidine being represented by the formula (I-c-3), with a reagentof formula (VII) wherein Q¹ is a radical of formula --C_(r) H_(2r) --T⁴H, said reagent being represented by the formula (VII-c). ##STR20##

The alkylation reactions are conveniently conducted in an inert organicsolvent such as, for example, an aromatic hydrocarbon, e.g., benzene,methylbenzene, dimethylbenzene, and the like; a C₁₋₆ alkanol, e.g.,methanol, ethanol, 1-butanol and the like; a ketone, e.g., 2-propanone,4-methyl-2-pentanone and the like; an ether, e.g., 1,4-dioxane,1,1'-oxybisethane, tetrahydrofuran and the like; N,N-dimethylformamide(DMF); N,N-dimethylacetamide (DMA); dimethyl sulfoxide (DMSO);nitrobenzene; 1-methyl-2-pyrrolidinone; and the like. The addition of anappropriate base such as, for example, an alkali metal carbonate orhydrogen carbonate, sodium hydride or an organic base such as, forexample, N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine may beutilized to pick up the acid which is liberated during the course of thereaction. In some circumstances the addition of a iodide salt,preferably an alkali metal iodide, is appropriate. Somewhat elevatedtemperatures may enhance the rate of the reaction.

The compounds of formula (I-b) can also be prepared by the reductiveN-alkylation reaction of (I-c-1) with an appropriate carbonyl-compoundof formula L^(2-a) ═C═O (VIII), said L^(2-a) ═C═O being a compound offormula L² --H wherein a --CH₂ -- radical is oxidated to a carbonylradical. ##STR21##

The compounds of formula (I-b), wherein L² is a radical of formula L¹--C_(r) H_(2r) --NR³ --C_(s) H_(2s) --, said compounds being representedby the formula (I-b-3) may alternatively be prepared by the reductiveN-alkylation reaction of a compound of formula (I), wherein L is aradical of formula HN(R³)--C_(s) H_(2s) --, (I-d), with an appropriatecarbonyl-compound of formula L¹ --(C_(r) H_(2r-1))═O, (IX), said L¹--(C_(r) H_(2r-l))═O being a compound of formula L¹ --C_(r) H_(2r) --Hwherein a --CH₂ -- radical is oxidated to a carbonyl radical. Thecompounds of formula (I-b-3) can also be prepared by the reductiveN-alkylation of an amine of formula (X), with a compound of formula (I)wherein L is a radical of formula O═(C_(s) H_(2s-1))--, said compoundbeing represented by the formula (I-e), and said O═(C_(s) H_(2s-1))--being a radical of formula H--C_(s) H_(2s) -- wherein a --CH₂ -- radicalis oxidated to a carbonyl radical. ##STR22##

Said reductive N-alkylation reaction may conveniently be carried out bycatalytically hydrogenating a mixture of the reactants in a suitablereaction-inert organic solvent according to art-known catalytichydrogenating procedures. The reaction mixture may be stirred and/orheated in order to enhance the reaction rate. Suitable solvents are, forexample, water; C₁₋₆ alkanols, e.g. methanol, ethanol, 2-propanol andthe like; cyclic ethers, e.g. 1,4-dioxane and the like; halogenatedhydrocarbons, e.g. trichloromethane and the like; N,N-dimethylformamide;dimethyl sulfoxide and the like; or a mixture of 2 or more of suchsolvents. The term "art-known catalytic hydrogenating procedures" meansthat the reaction is carried out under hydrogen atmosphere and in thepresence of an appropriate catalyst such as, for example,palladium-on-charcoal, platinum-on-charcoal and the like. In order toprevent the undesired further hydrogenation of certain functional groupsin the reactants and the reaction products it may be advantageous to addan appropriate catalyst-poison to the reaction mixture, e.g., thiopheneand the like.

The compounds of formula (I-b), wherein L is a radical of formula(b-1-a) wherein T is Z¹ --C(═X²)--NH--, Z¹ being as previouslydescribed, X² being O or S, and said compounds being represented by theformula (I-b-4), can generally be prepared by reacting an isocyanate orisothiocyanate of formula (I-f) with a reagent of formula (XI):##STR23##

The compounds of formula (I-b), wherein L² is a radical of formula(b-1-a), wherein T is --NH--C(═X²)--Y¹ --, Y¹ being as previouslydescribed, and the compounds of formula (I-b), wherein L² is a radicalof formula (b-1-a), wherein T is --NH--C(═X²)-- and s is 0, and thecompounds of formula (I-b), wherein L² is a radical of formula (b-2),wherein T¹ is --NH--C(═X²)--, said compounds being represented by theformula (I-b-5-a), respectively (I-b-5-b) and (I-b-5-c), can be preparedby reacting an isocyanate or isothiocyanate of formula (XII) with apiperidine of formula (I-c-4), respectively (I-c-1) and (I-c-5).##STR24## The reaction of (XI) with (I-f) and of (XII) with (I-c-4),respectively (I-c-1) and (I-c-5) may be conducted in a suitablereaction-inert solvent such as, for example, a hydrocarbon, e.g.,benzene, a ketone, e.g., acetone, a halogenated hydrocarbon, e.g.,dichloromethane, trichloromethane, an ether, e.g., 1,1'-oxybisethane,tetrahydrofuran and the like. Elevated temperatures may be suitable toenhance the rate of the reaction.

The compounds of formula (I-b), wherein L² is a radical of formula(b-1-a), wherein T is --C(═X²)--Y¹ --, and the compounds of formula(I-b), wherein L is a radical of formula (b-1-a), wherein s is 0 and Tis a radical of formula --C(═X²)--, and the compounds of formula (I-b)wherein L² is a radical of formula (b-2), wherein T¹ is --C(═X²)--, saidcompounds being represented by the formula (I-b-6-a), respectively(I-b-6-b) and (I-b-6-c), may be prepared by reacting a piperidine offormula (I-c-4), respectively (I-c-1) and (I-c-5) with a reagent offormula (XIII). ##STR25## The reaction of (XIII) with (I-c-4) ,respectively (I-c-1) and (I-c-5) may generally be conducted followingart-known esterification- or amidation reaction-procedures. For example,the carboxylic acid may be converted into a reactive derivative, e.g.,an anhydride or a carboxylic acid halide, which subsequently, is reactedwith (I-c-4), (I-c-1) or (I-c-5) or by reacting (XIII) and (I-c-4),respectively (I-c-1) and (I-c-5) with a suitable reagent capable offorming amides or esters, e.g., dicyclohexylcarbodiimide,2-chloro-1-methylpyridinium iodide and the like. Said reactions are mostconveniently conducted in a suitable solvent such as, for example, anether, e.g., tetrahydrofuran, a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane or a polar aprotic solvent, e.g.N,N-dimethylformamide. The addition of a base, e.g.N,N-diethylethanamine may be appropriate.

The compounds of formula (I-b), wherein L² is a radical of formula(b-1-a) wherein T is --Z¹ --C(═X)--Y¹ --, and the compounds of formula(I-b), wherein L² is a radical of formula (b-1-a) wherein s is 0 and Tis --Z¹ --(C═X)--, and the compounds of formula (I-b), wherein L² is aradical of formula (b-2) wherein T¹ is --Z¹ --C(═X)--, said compoundsbeing represented by the formula (I-b-7-a), respectively (I-b-7-b) and(I-b-7-c), can also be prepared by reacting (XI) with (I-c-4),respectively (I-c-1) and (I-c-5) in the presence of an appropriate >C═Xgenerating agent. ##STR26## An appropriate >C═X generating agent is, forexample, 1,1'-thiocarbonylbis[1H-imidazole],1,1'-carbonylbis[1H-imidazole], carbonic dichloride, carbonothioicdichloride, urea, thiourea, trichloroacetyl chloride, and the like. Thereaction of (XI) with (I-c-4), (I-c-1) or (I-c-5) is convenientlyconducted in a suitable solvent, such as, for example, a hydrocarbon,e.g., benzene, methylbenzene; an ether, e.g., 1,1'-oxybisethane,tetrahydrofuran; a halogenated hydrocarbon, e.g., dichloromethane,trichloromethane and the like. The addition of a base such as, forexample, an alkali metal carbonate or hydrogen carbonate or an organicbase, e.g., N,N-diethylethanamine and the like, may be appropriate.

The compounds of formula (I-b) wherein L² is a radical of formula (b-1),wherein s is an integer of from 2 to 6 inclusive, said compounds beingrepresented by the formula (I-g) can be prepared by reacting anappropriate alkene of formula (XIV) with a piperidine of formula(I-c-1). ##STR27##

The compounds of formula (I-b) wherein L² is a radical of formula L¹--C_(r) H_(2r) --T--C_(s'-2) H_(2s'-4) --CH(Y¹ H)--CH₂ --, wherein s' isan integer of from 2 to 6 inclusive, said compounds being represented bythe formula (I-h) may also be prepared by reacting a reagent of formula(XV) with a piperidine of formula (I-c-1). ##STR28## The reactions of(XIV) with (I-c-1), and (XV) with (I-c-1) may be conducted by stirringand, if desired, heating the reactants together. The said reactions maybe conducted in a suitable solvent such as, for example, an alkanone,e.g., 2-propanone, 4-methyl-2-propanone, an ether, e.g. tetrahydrofuran,1,1'-oxybisethane, an alcohol, e.g. methanol, ethanol, 1-butanol,N,N-dimethylformamide, N,N-dimethylacetamide and the like.

It is evident that the radical "--C₂₋₆ alkenyl--", the corresponding"--C₂₋₆ alkanediyl--"radical and the radical C_(2s'-2) H_(2s'-4) maybear the previously described substitutions of the radical --C_(s)H_(2s) --.

The compounds of formula (I) wherein L¹ is Het, said compounds beingrepresented by the formula (I-i), may also be prepared followingprocedures for preparing ring systems which are known in the art oranalogous procedures thereof. A number of such cyclization procedureswill be described hereinafter.

The bivalent radical K used in the description of these cyclizationreactions has the following meaning: ##STR29## and the radicals (e-1-a),(e-2), (e-3), (e-5-a), (e-6), (e-7) and (e-8) also used in thedescription of these cyclization reactions have the following meaning:##STR30## X², R¹¹, R¹³, R¹⁴, R¹⁵, R¹⁶, R²⁰, R²¹, R²², R²³, R²⁴, G¹, G³,G⁴, G⁵ and G⁶ have the same meaning as defined hereinabove for theparticularly preferred compounds.

For example, the compounds of formula (I-i) wherein Het is an optionallysubstituted imidazolyl radical, said compounds being represented by theformula (I-i-1), can be prepared by the cyclization reaction of anappropriate N-(2,2-diC₁₋₆ alkyloxyethyl)imidamide derivative of formula(XVI). ##STR31## wherein R²⁵, R²⁶ and R²⁷ are each independentlyoptional substituents of the imidazole ring.

Said cyclization reaction may conveniently be conducted in a suitablesolvent in the presence of an appropriate acid such as, for example,hydrochloric, hydrobromic and the like acids. Elevated temperatures mayenhance the rate of the reaction.

The compounds of formula (I-i) wherein Het is an optionally substitutedthiazolyl radical, being optionally condensed with a five-orsix-membered hetero- or carbocyclic ring, may be prepared by a number ofcyclization reactions, yielding, depending upon the case, compoundswhich may be represented by the formula (I-i-2) or (I-i-3). ##STR32##

R²⁸, R²⁹, R³⁰ and R³¹ are each independently optional substituents ofthe said thiazolyl ring, or, where in the compounds of formula (I-i-2)said thiazolyl ring is condensed with a five- or six-membered hetero- orcarbocyclic ring, R²⁸ and R²⁹ taken together may form a bivalent radicalof formula G⁴.

Further, where Het is a radical of formula (e-1-a), said Het may beformed by condensing an intermediate (XXI) with a >C═X² generatingagent, e.g. urea, thiourea, 1,1'-carbonylbis[1H-imidazole], C₁₋₆ alkylcarbonohalidate, phosgene, thiophosgene, trichloromethyl carbonohalidateand the like. ##STR33##

The compounds of formula (I-i-4) wherein R¹¹ is hydrogen mayadditionally be prepared by cyclizing an intermediate of formula##STR34## reacting a reagent (XXIII) with an amine (XXIV). ##STR35## Thereaction of (XXI) with the >C═X² generating agent and the cyclization of(XXII) may conveniently be conducted in a suitable solvent such as, forexample, an ether, e.g. 1,1-oxybisethane, tetrahydrofuran, anhalogenated hydrocarbon, e.g. dichloromethane, trichloromethane, ahydrocarbon, e.g. benzene, methylbenzene, an alcohol, e.g. methanol,ethanol, a ketone, e.g. 2-propanone, 4-methyl-2-pentanone,N,N-dimethylformamide, N,N-dimethylacetamide, or mixtures of suchsolvents, optionally in the presence of an appropriate base such as, forexample, N,N-diethylethanamine, an alkali or earth alkaline metalcarbonate or hydrogen carbonate. In order to enhance the reaction rate,it may be suitable to heat the reaction mixture.

Further, where Het is a radical of formula (e-2), said Het may begenerated by cyclizing an intermediate (XXV) with an acid (XXVI) or asuitable functional derivative thereof, thus preparing a compound offormula (I-i-5). Alternatively an intermediate (XXVII) may be condensedwith an aromatic amino acid or -thioacid of formula (XXVIII), preparingalso a compound (I-i-5). ##STR36## The reaction of (XXV) with (XXVI) andof (XXVII) with (XXVIII) may be conducted in a suitable reaction-inertsolvent, such as, for example, a hydrocarbon, e.g. benzene,methylbenzene, an alcohol, water. In some instances it may beappropriate to use higher temperatures in order to reduce the reactiontime.

Where Het is a radical of formula (e-3), wherein R¹⁶ is hydrogen and R¹⁵is a radical of formula R^(15-a) --CH₂ --, said Het may be formed byreacting a compound (XXIX)s with an appropriate acetylene derivative(XXX), thus preparing a compound of formula (I-i-6).

Additionally, where Het is a radical of formula (e-3), said Het may beformed by reacting (XXIX) with a ketone of formula (XXXI), thuspreparing a compound of formula (I-i-7). ##STR37## The reaction of(XXIX) with (XXX) may be conducted in a suitable solvent such as, forexample, an alcohol, e.g. methanol, ethanol, while the reaction of(XXIX) with (XXXI) may be conducted in a suitable solvent preferably inthe presence of an organic acid such as, for example, ethanedioic acidand the like. Elevated temperatures may also be appropriate to shortenthe reaction time.

Additionally, where Het is a radical (e-5-a), said Het may be created bycondensing a reagent (XXXII) with an intermediate (XXXIII), thus givinga compound (I-i-8). ##STR38##

Where Het is a radical (e-6) being connected to K by the G⁴ containingring and bearing a 2-mercaptosubstituent, said Het may be formed duringthe cyclization of an intermediate (XXXII) with CS₂, thus preparing acompound (I-i-9). ##STR39##

Where Het is a radical of formula (e-7) being connected to K either bythe G⁵ containing ring or by the imidazole ring, said Het is formedduring the condensation reaction of a reagent (XXXV) with anintermediate (XXXVI) respectively by the cyclodesulfurization reactionof an intermediate (XXXVII), thus preparing a compound (I-i-10)respectively (I-i-11). ##STR40## The reactions of (XXXII) with (XXXIII),of (XXXIV) with CS₂ and (XXXV) with (XXXVI) may conveniently conductedin a suitable reaction-inert solvent, such as for example one of thesolvents given hereinabove for the preparation of (I-i-4) optionally inthe presence of an appropriate base, e.g. one of the bases alsodescribed for the preparation of (I-i-4); higher temperature may be usedto enhance the reaction rate.

The cyclodesulfurization of (XXXVII) may be carried out by the reactionof (XXXVII) with an appropriate alkyl halide, preferably iodomethane inan appropriate reaction-inert organic solvent, e.g., a C₁₋₆ alkanol suchas methanol, ethanol, 2-propanol and the like. Otherwise, thecyclodesulfurization reaction may be carried out by the reaction of(XXXVII) with an appropriate metal oxide or salt in an appropriatesolvent according to art-known procedures. For example, the compounds offormula (I) can easily be prepared by the reaction of (XXXVII) with anappropriate Hg(II) or Pb(II) oxide or salt, such as, for example HgO,HgCl₂, Hg(OAc)₂, PbO or Pb(OAc)₂. In certain instances it may beappropriate to supplement the reaction mixture with a small amount ofsulfur. Even so methanediimines, especiallyN,N'-methanetetraylbis[cyclohexanamine] may be used ascyclodesulfurizing agents.

Where Het is a radical (e-8), said Het may be formed during thecondensation of an intermediate (XXVIII) with a >C═X² generating agent,following the same procedures as previously described for thepreparation of (I-i-4) starting from (XXXIII). ##STR41##

The compounds of formula (I) can also be converted into each otherfollowing art-known procedures of functional grouptransformation. Someexamples will be cited hereinafter.

The compounds of formula (I), wherein --B-- is --S-- may be convertedinto the corresponding compounds of formula (I), wherein --B-- is --SO--or --SO₂ -- by an appropriate oxidation reaction, e.g. by reacting theformer compounds with a suitable oxidating agent such as, for example,potassium periodate, a peroxide, e.g. 3-chlorobenzenecarboperoxoic acid,hydrogen peroxide, and the like, in a suitable solvent such as, forexample, an ether, e.g. tetrahydrofuran, 1,1'-oxybisethane, ahydrocarbon, e.g. benzene, a halogenated hydrocarbon, e.g.dichloromethane, trichloromethane and the like. In the instance where asulfinyl is desired, said oxidation reaction is preferably conducted atlower temperature with approximately one equivalent of the oxidatingagent, while where a sulfonyl is desired, said oxidation reaction may beconducted at room or elevated temperature with an excess of oxidatingagent.

The compounds of formula (I) having a nitro substituent can be convertedinto the corresponding amines by stirring and, if desired, heating thestarting nitro-compounds in a hydrogen-containing medium in the presenceof a suitable amount of an appropriate catalyst such as, for example,platinum-on-charcoal, palladium-on-charcoal, Raney-nickel and the likecatalysts. Suitable solvents are, for example, alcohols, e.g., methanol,ethanol and the like.

In an analogous procedure, the compounds of formula (I) having a cyanosubstituent, can be converted into the corresponding aminomethylcontaining compounds.

The compounds of formula (I) having an hydroxy substituent may beconverted into the corresponding halo compounds following art-knownhalogenating procedures, e.g., by reacting the former compounds with asuitable halogenating agent, e.g. thionyl chloride, phosphoryl chloride,phosphor trichloride, phosphor pentachloride, thionyl bromide, phosphortribromide and the like.

The compounds of formula (I) containing an ester group may be convertedinto the corresponding carboxylic acids following art-knownsaponification procedures, e.g, by treating the said compounds with anaqueous alkaline solution or with an aqueous acidic solution.

The compounds of formula (I) containing a Het substituted with a thioxogroup can be converted into the corresponding oxo compounds followingart-known procedures, for example, by treating the said thioxocontaining compounds with a peroxide, e.g. hydrogen peroxide in asuitable alkaline medium, e.g. an aqueous alkali metal hydroxidesolution which may be mixed with an organic solvent, such as, forexample, methanol, ethanol and the like.

The compounds of formula (I) containing an unsaturated Het can beconverted into the corresponding saturated form following art-knownreducing procedures, e.g. by treating the said compounds with hydrogenin the presence of a suitable catalyst such as, for example,platinum-on-charcoal, palladium-on-charcoal an the like catalysts.

Halo atoms substituted on aryl groups may be replaced by hydrogenfollowing art-known hydrogenolysis procedures, i.e. by stirring and, ifdesired, heating the starting compounds in a suitable solvent underhydrogen atmosphere in the presence of an appropriate catalyst, e.g.,palladium-on-charcoal and the like catalysts. Said halo atoms may alsobe replaced by a C₁₋₆ alkyloxy or a C₁₋₆ alkylthio substituent byreacting the starting halo-compound with an appropriate alcohol orthioalcohol or, preferably, an alkali- or earth alkaline metal salt oran appropriate alcohol or thioalcohol in a suitable solvent. Said haloatoms may also be replaced by a hydroxy substituent by treating thestarting compounds with an aqueous acidic solution, e.g. an aqueoushydrochloric or hydrobromic solution.

C₁₋₆ alkyloxy and C₁₋₆ alkylthio radicals substituted on aryl may beconverted into the corresponding hydroxy or thiol radicals by treatingthem with an aqueous acidic solution, e.g. an aqueous hydrochloric orhydrobromic solution.

The compounds of formula (I) containing an imino group, e.g. where NR¹,NR³, NR⁴ or NR⁵ is NH, or an amino group, e.g. where AR¹, AR² or Het issubstituted with an amino group, the hydrogen atom in said imino oramino may be replaced by a suitable substituent following art-knownprocedures such as, for example, N-alkylation, reductive N-alkylation,acylation and the like methods. A number of such procedures will bedescribed hereinafter in more detail. For example, C₁₋₆ alkyl groups orsubstituted C₁₋₆ alkyl groups may be introduced by reacting the startingcompounds with an appropriate N-alkylating agent following theprocedures described hereinabove for the N-alkylation reactions of (VII)with (I-c), or by reacting the starting compounds with an appropriatecarbonyl-compound following the reductive N-alkylation proceduresdescribed hereinabove for the reductive N-alkylations of (I-c-1) with(VIII), (I-d) with (IX) and (I-e) with (X).

C₁₋₆ alkylcarbonyl, Ar² -carbonyl and the like groups may be introducedby reacting the starting amine with an appropriate carboxylic acid or aderivative thereof such as, for example, an acid halide, acid anhydrideand the like.

C₁₋₆ alkyloxycarbonyl and Ar² -oxycarbonyl groups can be introduced byreacting the starting amine compound with an appropriatecarbonohalidate, e.g. ethyl carbonohalidate, phenylmethylcarbonohalidate and the like.

Ar² --NH--CO, Ar² --NH--CS, (C₁₋₆ alkylamino)--CO-- (C₁₋₆alkylamino)--CS--, and the like groups can conveniently introduced byreacting the starting amine compound with an appropriate isocyanate orisothiocyanate following the procedures described hereinabove for thepreparation of (I-b-4), (I-b-5-a), (I-b-5-b) and (I-b-5-c).

The compounds of formula (I) containing a substituted nitrogen atom maybe converted into the corresponding compounds of formula (I) whereinsaid nitrogen bears a hydrogen atom following art-known methods forpreparing N-H groups such as, for example:

1. where said nitrogen is substituted with an Ar² --CH₂ group, bytreating the starting compounds with hydrogen in the presence of asuitable catalyst, e.g. palladium-on-charcoal, platinum-on-charcoal, inan appropriate solvent;

2. or, where said nitrogen is substituted with a sulfonyl group, e.g.C₁₋₆ alkylsulfonyl and Ar² -sulfonyl, by treating the starting compoundswith an aqueous acidic solution preferably in the presence of a catalystsuch as, for example, phenol, methoxybenzene and the like;

3. or, where said nitrogen atoms are substituted with an Ar² -carbonylgroup by treating the starting compounds with an aqueous basic solution,e.g. an alkali metal hydroxide solution;

4. where said nitrogen is substituted with C₁₋₆ alkyloxy carbonyl or Ar²-oxycarbonyl, by treating the starting compounds with an aqueous acidicor aqueous basic solution optionally in admixture with an organicsolvent or where said nitrogen atom is substituted with Ar²-oxycarbonyl, by catalytically hydrogenating the starting materials in asuitable solvent.

The compounds of formula (I) containing a nitrogen atom substituted withAr² --CH₂ -- may be converted into the corresponding compounds wheresaid nitrogen is substituted with C₁₋₆ alkyloxycarbonyl, for example bytreating the former compounds with a C₁₋₆ alkyl carbonohalidate in thepresence of a suitable solvent and, if desired, in the presence of anappropriate base.

The compounds of formula (I) containing a mercapto group may beconverted into the corresponding isothiocyanato containing compounds bytreating the starting amino compounds with CS₂ in the presence ofN,N'-methanetetraylbis[cyclohexanamine].

The compounds of formula (I) containing a --CH₂ --C(═O)-- fragment canbe converted into the corresponding compounds of formula (I) containinga --CH(halo)--C(═O)-- fragment following art-known halogenatingprocedures, e.g. by treating the starting compound with a halogen.

In all of the foregoing and in the following preparations, the reactionproducts may be isolated from the reaction mixture and, if necessary,further purified according to methodologies generally known in the art.

The compounds of formula (I) have basic properties and, consequently,they may be converted to their therapeutically active non-toxic acidaddition salt forms by treatment with appropriate acids, such as, forexample, inorganic acids, such as hydrohalic acid, e.g. hydrochloric,hydrobromic and the like, and sulfuric acid, nitric acid, phosphoricacid and the like; or organic acids, such as, for example, acetic,propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,ethanedioic, propanedioic, butanedioic, (Z)-2-butenedioic,(E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely the salt form can be converted by treatment with alkali intothe free base form.

Some intermediates and starting materials in the foregoing preparationsare known compounds which may be prepared according to art-knownmethodologies of preparing said or similar compounds and others are new.A number of such preparation methods will be described hereinafter inmore detail.

The intermediates of formula (II), wherein B is CH₂, X¹ is NH and W isC₁₋₆ alkyloxy, said intermediates being represented by the formula(II-c), can be prepared by reacting a (cyanomethyl)piperidine of formula(XXXIX) with an alcohol, e.g. methanol, ethanol and the like, in thepresence of an acid, e.g. hydrochloric acid. ##STR42##

The intermediates of formula (IV) may be prepared by a reductionreaction of an appropriate 4-piperidinone, and, if desired, followed byan appropriate art-known groupstransformation procedure, e.g., where acompound of formula (V-b) is desired, by reacting the thus obtainedalcohol with thionyl chloride, methylsulfonyl chloride and the like inorder to obtain an appropriate leaving group.

The intermediates of formula (VI-a) can be prepared by the proceduresdescribed in, for example, European Patent Publication Nos. 0,099,139;0,145,037 and 0,144,101.

The intermediates of formula (VII) can conveniently be preparedfollowing art-known procedures as described in, for example, U.S. Pat.Nos. 4,335,127, 4,342,870 and European Patent Publication Number0,070,053.

From formula (I) it is evident that the compounds of this invention mayhave several asymmetric carbon atoms in their structure. Each of thesechiral centers may be present in a R- and a S-configuration, this R- andS-notation being in correspondence with the rules described by R. S.Cahn, C. Ingold and V. Prelog in Angew. Chem., Int. Ed. Engl., 5, 385,511 (1966).

Pure stereochemically isomeric forms of the compounds of formula (I) maybe obtained by the application of art-known procedures. Diastereoisomersmay be separated by physical separation methods such as selectivecrystallization and chromatographic techniques, e.g., counter currentdistribution, and enantiomers may be separated from each other by theselective crystallization of their diastereomeric salts with opticallyactive acids.

Pure stereochemically isomeric forms may also be derived from thecorresponding pure stereochemically isomeric forms of the appropriatestarting materials, provided that the reaction occursstereospecifically.

It is evident that the cis and trans diastereomeric racemates may befurther resolved into their optical isomers, cis(+), cis(-), trans(+)and trans(-) by the application of methodologies known to those skilledin the art.

Stereochemically isomeric forms of the compounds of formula (I) arenaturally intended to be embraced within the scope of the invention.

The compounds of the present invention possess useful pharmacologicalproperties and are active as antihistamines and asserotonin-antagonists. This is clearly demonstrated by the results ofthe "Protection of rats from compound 48/80-induced lethality" test.

In view of their antihistaminic properties, the compounds of formula (I)and their acid-addition salts are very useful in the treatment ofallergic diseases such as, for example, allergic rhinitis, allergicconjunctivities, chronic urticaria, allergic astma and the like.

In view of their useful pharmacological properties the subject compoundsmay be formulated into various pharmaceutical forms for administrationpurposes. To prepare the pharmaceutical compositions of this invention,an effective amount of the particular compound, in base or acid additionsalt form, as the active ingredient is combined in intimate admixturewith a pharmaceutically acceptable carrier, which carrier may take awide variety of forms depending on the form of preparation desired foradministration. These pharmaceutical compositions are desirably inunitary dosage form suitable, preferably, for administration orally,rectally, percutaneously, or by parenteral injection. For example, inpreparing the compositions in oral dosage form, any of the usualpharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups, elixirs and solutions; orsolid carriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example, maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspension may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. In thecompositions suitable for percutaneous administration, the carrieroptionally comprises a penetration enhancing agent and/or a suitablewettable agent, optionally combined with suitable additives of anynature in minor proportions, which additives do not introduce asignificant deleterious effect on the skin. Said additives mayfacilitate the administration to the skin and/or may be helpful forpreparing the desired compositions. These compositions may beadministered in various ways, e.g., as a transdermal patch, as aspot-on, as an ointment. Acid addition salts of (I) due to theirincreased water solubility over the corresponding base form, areobviously more suitable in the preparation of aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The present invention is also related with a method of treating allergicdiseases in warm-blooded animals suffering from said allergic diseasesby administering an effective anti-allergic amount of a compound offormula (I) or a pharmaceutically acceptable acid addition salt thereof.

Those of skill in treating allergic diseases in warm-blooded animalscould easily determine the effective amount from the test resultspresented hereinafter. In general it is contemplated that an effectiveamount would be from 0.1 mg to 100 mg, more preferably from 1 to 50 mg.

The following examples are intented to illustrate and not to limit thescope of the present invention in all its aspects. Unless otherwisestated all parts therein are by weight.

EXPERIMENTAL PART A. Preparation of Intermediates Example 1

A mixture of 3.7 parts of 2-pyridinemethanamine, 4.1 parts of4,6-dichloropyrimidin-5-amine, 3.03 parts of N,N-diethylethanamine and150 parts of water was stirred for 8 hours at room temperature. Aftercooling, the whole was stirred overnight. The product was filtered off,washed with water and dried overnight in vacuo at 80° C., yielding 5.35parts (90.8%) of 6-chloro-N⁴ -(2-pyridinylmethyl)-4,5-pyrimidinediamine;mp. 140.3° C. (interm. 1).

In a similar manner there were also prepared:

6-chloro-N⁴ -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine; mp. 244.4°C. (interm. 2);

6-chloro-N⁴ -(2-furanylmethyl)-4,5-pyrimidinediamine mp. 138.7° C.(interm. 3);

6-chloro-N⁴ -(2-thienylmethyl)-4,5-pyrimidinediamine; mp. 165.5° C.(interm. 4);

6-chloro-N⁴ -[(5-methyl-2-furanyl)methyl]-4,5-pyrimidinediamine (interm.5);

6-chloro-N⁴ -(2-pyrazinylmethyl)-4,5-pyrimidinediamine (interm. 6);

6-chloro-N⁴ -(4-thiazolylmethyl)-4,5-pyrimidinediamine; mp. 145.5° C.(interm. 7);

6-chloro-N⁴ -[(4-methoxyphenyl)methyl]-4,5-pyrimidinediamine; mp. 183.5°C. (interm. 8); and

N⁴ -[(4-fluorophenyl)methyl]-6-methyl-4,5-pyrimidinediamine; (interm.9).

In a similar manner there is also prepared: 6-chloro-N⁴-[(2,4-dimethylphenyl)methyl]-4,5-pyrimidinediamine; (interm. 10).

Example 2

To a stirred mixture of 20.2 parts of 4,5-pyrimidinediamine, 40 parts ofpyridine and 144 parts of N,N-dimethylformamide was added dropwise asolution of 24.2 parts of 4-fluorobenzoyl chloride in 36 parts ofN,N-dimethylformamide at 10° C. Upon completion, stirring was continuedfor 30 minutes at room temperature. 600 Parts of water were added. Theproduct was filtered off and dried, yielding 30 parts (70%) ofN-(4-amino-5-pyrimidinyl)-4-fluorobenzamide (interm. 11).

To a stirred mixture of 30 parts ofN-(4-amino-5-pyrimidinyl)-4-fluorobenzamide and 360 parts oftetrahydrofuran were added portionwise 9.86 parts of lithiumtetrahydroaluminate under nitrogen atmosphere. The mixture was stirredfor 6 hours. Another portion of 10 parts of lithium tetrahydroaluminatewas added portionwise and stirring was continued for 2 hours at roomtemperature. The reaction mixture was decomposed with water. The layerswere separated. The aqueous phase was extracted with tetrahydrofuran.The combined organic layers were dried, filtered and evaporated. Theresidue was crystallized from acetonitrile. The product was filtered offand dried, yielding 18 parts (63.5%) of

N⁵ -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine (interm. 12).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

N-(4-amino-6-hydroxy-5-pyrimidinyl)-4-fluorobenzamide (interm. 13); and

6-amino-5-[[(4-fluorophenyl)methyl]amino]-4-pyrimidinol (interm. 14).

Example 3

A mixture of 62.2 parts of 6-chloro-N⁴-(2-pyridinylmethyl)-4,5-pyrimidinediamine, 3 parts of a solution ofthiophene in methanol 4%, 20 parts of calcium oxide and 400 parts ofmethanol was hydrogenated at normal pressure and at 50° C. with 5 partsof palladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated, yielding 63.5 parts (100%) of N⁴-(2-pyridinylmethyl)-4,5-pyrimidinediamine as a residue (interm. 15).

In a similar manner there were also prepared:

N⁴ -[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine as a residue (interm.16);

N⁴ -(2-furanylmethyl)-4,5-pyrimidinediamine; mp. 116.4° C. (interm. 17);

N⁴ -(2-thienylmethyl)-4,5-pyrimidinediamine (interm. 18);

N⁴ -[(5-methyl-2-furanyl)methyl]-4,5-pyrimidinediamine (interm. 19);

N⁴ -(2-pyrazinylmethyl)-4,5-pyrimidinediamine as a residue (interm. 20);

N⁴ -[(4-methoxyphenyl)methyl]-4,5-pyrimidinediamine (interm. 21); and

N⁴ -(4-thiazolylmethyl)-4,5-pyrimidinediamine (interm. 22).

In a similar manner there is also prepared:

N⁴ -[(2,4-dimethylphenyl)methyl]-4,5-pyrimidinediamine (interm. 23).

Example 4

A mixture of 8.72 parts of N⁴-[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine, 63 parts of carbondisulfide and 45 parts of N,N-dimethylformamide was stirred for 3 hoursat reflux temperature. After cooling, the reaction mixture was pouredinto water. The precipitated product was filtered off and dried,yielding 10.1 parts (78.9%) of9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol (interm. 24).

To a stirred mixture of 4.6 parts of potassium hydroxide and 200 partsof water were added portionwise 1.7 parts of iodomethane, followed bythe dropwise addition of 3.8 parts of9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol. Upon complete addition,the whole was stirred for 2 hours at room temperature. The precipitatedproduct was filtered off and dried, yielding 3.45 parts (73.9%) of9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine; mp. 167.1° C.(interm. 25).

Example 5

A mixture of 26 parts of methyl 3-methyl-4-oxo-1-piperidinecarboxylate,16.5 parts of benzenemethanamine, 2 parts of a solution of thiophene inethanol 4% and 200 parts of methanol was hydrogenated at normal pressureand at room temperature with 3 parts of palladium-on-charcoal catalyst10%. After the calculated amount of hydrogen was taken up, the catalystwas filtered off and the filtrate was evaporated to dry, yielding 40.2parts of methyl 3-methyl-4-[(phenylmethyl)amino]-1-piperidinecarboxylateas a residue (interm. 26).

A mixture of 40 parts of methyl3-methyl-4-[(phenylmethyl)amino]-1-piperidinecarboxylate and 160 partsof methanol was hydrogenated at normal pressure and at room temperaturewith 2 parts of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen was taken up, the catalyst was filtered off and thefiltrate was evaporated to dry. The residue was distilled (bp. 80° C. at0.1 mm. pressure). The distillate was further purified bygas-chromatography (at 215° C. and at 10 lbs/sq. inch), yielding 8.6parts of methyl 4-amino-3-methyl-1-piperidinecarboxylate (interm. 27)

To a stirred and cooled (-10° C.) mixture of 138.6 parts of carbondisulfide, 113.8 parts of N,N'-methanetetraylbis[cyclohexanamine] and450 parts of tetrahydrofuran were added dropwise 106 parts of methyl4-amino-3-methyl-1-piperidinecarboxylate at this low temperature. Thereaction mixture was allowed to attain room temperature. After stirringfor 1 hour at room temperature, the mixture was evaporated and theresidue was stirred in 2,2'-oxybispropane. The precipitate was filteredoff and the filtrate was evaporated, yielding 141.1 parts (100%) ofmethyl cis-4-isothiocyanato-3-methyl-1-piperidinecarboxylate as aresidue (interm. 28).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared: methyl(cis+trans)-methyl 4-amino-3-methyl-1-piperidinecarboxylate; bp.136°-140° C. (water-jet) (interm. 29); and methyl(cis+trans)-4-isothiocyanato-3-methyl-1-piperidinecarboxylate as aresidue (interm. 30).

Example 6

A mixture of 42.5 parts of N⁴ -(2-furanylmethyl)-4.5-pyrimidinediamine,50.5 parts of ethyl 4-isothiocyanato-1-piperidinecarboxylate and 630parts of tetrahydrofuran was stirred for 48 hours at reflux temperature.After cooling, the product was filtered off, washed with tetrahydrofuranand 1,1'-oxybisethane and dried, yielding 86.4 parts (96.2%) of ethyl4-[[[[4-[(2-furanylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]-amino]-1-piperidinecarboxylate(interm. 31).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR43##                                                                                                           isomeric                                                                            mp.                              No.                                                                              L      R.sup.2                                                                           R.sup.1      A.sup.1A.sup.2A.sup.3A.sup.4                                                              form  °C.                       __________________________________________________________________________    32 C.sub.2 H.sub.5 OCO                                                                  H   4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC        --    --                               33 C.sub.2 H.sub.5 OCO                                                                  H   2-thienyl-CH.sub.2                                                                         NCNC        --    --                               34 C.sub.2 H.sub.5 OCO                                                                  H   2-pyridinyl-CH.sub.2                                                                       NCNC        --    --                               35 C.sub.6 H.sub.5 CH.sub.2                                                             H   4-FC.sub.6 H.sub.4CH.sub.2                                                                 CNCN        --    --                               36 C.sub.2 H.sub.5 OCO                                                                  H   (5-CH.sub.3 -2-furanyl)-CH.sub.2                                                           NCNC        --    --                               37 C.sub.2 H.sub.5 OCO                                                                  H   2-pyrazinyl-CH.sub.2                                                                       NCNC        --    --                               38 CH.sub.3 OCO                                                                         3-CH.sub.3                                                                        4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC        cis   --                               39 CH.sub.3 OCO                                                                         3-CH.sub.3                                                                        4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC        cis + trans                                                                         --                               40 C.sub.2 H.sub.5 OCO                                                                  H   4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                        NCNC        --    --                               41 C.sub.2 H.sub.5 OCO                                                                  H   4-thiazolyl-CH.sub.2                                                                       NCNC        --    --                               __________________________________________________________________________

In a similar manner there were also prepared:

N-(4-amino-6-hydroxy-5-pyrimidinyl-N-[(4-fluorophenyl)methyl)-N'-[1-(phenylmethyl)-4-piperidinyl]thiourea;mp. 192.9° C. (interm. 42); and

ethyl4-[[[(4-amino-6-hydroxy-5-pyrimidinyl)[(4-fluorophenyl)methyl]amino]-thioxomethyl]amino]-1-piperidinecarboxylate(interm. 43).

In a similar manner there is also prepared:

ethyl4-[[[4-[[(2,4-dimethylphenyl)methyl]amino]-5-pyrimidinyl]aminothioxomethyl]amino]-1-piperidinecarboxylate(interm. 44).

Example 7

A mixture of 52.4 parts of 1-(phenylmethyl)-4-piperidineacetic acidhydrochloride, 38.7 parts of N⁴-[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine and 765 parts ofphosphoryl chloride was stirred and refluxed for 30 minutes. Thereaction mixture was evaporated. The residue was decomposed with icewater. The product was extracted with dichloromethane after treatmentwith sodium hydroxide. The extract was washed with water, dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 37 parts (61%) ofN-[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]-1-(phenylmethyl)-4-piperidineacetamide;mp. 157.3° C. (interm. 45).

Example 8

To a stirred mixture of 14.2 parts of isocyanatoethane, 29.2 parts ofsodium azide and 135 parts of dry tetrahydrofuran was added a solutionof 39 parts of aluminum chloride in 225 parts of dry tetrahydrofuran.Stirring was continued overnight at reflux temperature. The reactionmixture was cooled and acidified with a hydrochloric acid solution 6N.The whole was evaporated to dry and the product was extracted four timeswith 2-propanone. The combined extracts were dried, filtered andevaporated. The residue was dried overnight, yielding 18 parts (65%) of1-ethyl-1,4-dihydro-5H-tetrazol-5-one (interm. 46).

To a stirred solution of 109 parts of 1,2-dibromoethane and 21.2 partsof sodium carbonate in 5 parts of water and 18 parts ofN,N-dimethylformamide were added dropwise a solution of 22.5 parts of1-ethyl-1,4-dihydro-5N-tetrazol-5-one in 5 parts of water and 27 partsof N,N-dimethylformamide at about 40° C. Upon completion, stirring wascontinued overnight at 40° C. The organic phase was separated, dried anddistilled, yielding 9.8 parts (22%) of1-(2-bromoethyl)-4-ethyl-1,4-dihydro-5H-tetrazol-5-one; bp. 110° C. at0.1 mm pressure (interm. 47).

Example 9

A mixture of 50 parts of 2-thiazolamine, 76 parts of3-acetyl-4,5-dihydro-2(3H)-furanone, 1.2 parts of concentratedhydrochloric acid and 270 parts of methylbenzene was stirred andrefluxed for 2 hours using a water-separator. The reaction mixture wascooled and 340 parts of phosphoryl chloride were added at a temperaturebetween 20° and 30° C. The whole was heated slowly to 100°-110° C. andstirring was continued for 2 hours at this temperature. The reactionmixture was evaporated and the residue was poured into a mixture ofcrushed ice and ammonium hydroxide. The product was extracted withtrichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol (95:5 by volume) as eluent. Thepure fractions were collected and the eluent was evaporated. The residuewas crystallized from a mixture of 2-propanol and 1,1'-oxybisethane,yielding 36 parts of yielding 36 parts of6-(2-chloroethyl)-7-methyl-5H-triazolo[3,2-a]pyrimidin-5-one (interm.48).

B. Preparation of Final compounds Example 10

A mixture of 20.65 parts of 1-(phenylmethyl)-4-piperidineacetic acidhydrochloride, 19.5 parts of 6-chloro-N⁴-[(4-fluorophenyl)methyl]-4,5-pyrimidinediamine and 510 parts ofphosphoryl chloride was stirred and refluxed for 13 hours. The reactionmixture was evaporated. The residue was poured into ice water. The wholewas treated with sodium hydroxide. The product was extracted with4-methyl-2-pentanone. The extract was washed with water, dried, filteredand evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (97:3 by volume) as eluent. The first fraction wascollected and the eluent was evaporated, yielding 23.6 parts (75%) of6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purineas an oily residue (compound 1).

In a similar manner there was also prepared:6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-7H-purine(compound 2); and9-[(4-fluorophenyl)methyl]-6-methyl-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purineas an oily residue (compound 3).

Example 11

A mixture of 36 parts ofN-[4-[[(4-fluorophenyl)methyl]amino[-5-pyrimidinyl]-1-(phenylmethyl)-4-piperidineacetamideand 935 parts of phosphoryl chloride was stirred and refluxed for 8hours. After cooling, the reaction mixture was evaporated. The residuewas decomposed in ice water. The whole was treated with a sodiumhydroxide solution. The product was extracted with 4-methyl-2-pentanone.The extract was dried, filtered and evaporated. The residue was purifiedby column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (97:3 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was stirred in 2,2'-oxybispropane. The productwas filtered off and crystallized from acetonitrile. The product wasfiltered off and dried, yielding 10.6 parts (30.4%) of9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl-9H-purine;mp. 136.4° C. (compound 4).

Example 12

A mixture of 12.6 parts of 1-(phenylmethyl)-4-piperidinol, 3.2 parts ofa sodium hydride dispersion 50% and 200 parts of N,N-dimethylacetamidewas stirred for 1 hour at room temperature. 18 Parts of9-[(4-fluorophenyl)methyl]-8-(methylthio)-9H-purine were addedportionwise and upon completion, stirring was continued for 4 hours atroom temperature. The reaction mixture was poured into water. Theproduct was filtered off and taken up in trichloromethane. The organiclayer was washed with water and filtered over diatomaceous earth. Thefiltrate was dried, filtered and evaporated. After crystallization fromacetonitrile, the product was filtered off and dried, yielding 16.75parts (61.1%) of9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine;mp. 117.0° C. (compound 5).

Example 13

To a stirred mixture of 13 parts of9-[(4-fluorophenyl)methyl]-9H-purine-8-thiol and 300 parts of water wereadded 2 parts of sodium hydroxide. The reaction mixture was filteredover diatomaceous earth. After evaporation, the residue was taken up inmethylbenzene and the solvent was evaporated again (this was repeatedtwice). The residue was taken up in 270 parts of N,N-dimethylacetamideand 19.3 parts of 1-[(4-methylphenyl)sulfonyl]-4-piperidinolmethanesulfonate (ester) were added. The whole was stirred over weekendat 60° C. The reaction mixture was poured into water and the product wasextracted with 4-methyl-2-pentanone. The extract was washed with water,dried, filtered and evaporated, yielding 27 parts (100%) of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidine(compound 6).

Example 14

A mixture of 4 parts of ethyl4-[[[[4-[(2-furanylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]-amino]-1-piperidinecarboxylate,6 parts of mercury(II) oxide and 80 parts of ethanol was stirred for 2hours at reflux temperature. The whole was filtered while hot overHyflo® and the filtrate was evaporated. The residue was crystallizedfrom a mixture of acetonitrile and ethanol. The product was filtered offand dried, yielding 0.8 parts (21.5%) of ethyl4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate;mp. 171.9° C. (compound 7).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there was also prepared:

ethyl4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinecarboxylate;mp. 174.5° C. (compound 8).

Example 15

A mixture of 24 parts of ethyl4-[[[[4-[(phenylmethyl)amino]-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate,24 parts of mercury(II) oxide and 240 parts of methanol, saturated withammonia was stirred overnight at reflux temperature. The reactionmixture was filtered while hot and the filtrate was evaporated. Theresidue was taken up in a mixture of trichloromethane and ethanol. Afterwashing with water, the organic layer was evaporated and the residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 20.3 parts (92.1%) of ethyl4-[[9-(phenylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate; mp.156.9° C. (compound 9).

In a similar manner there were also prepared:

ethyl4-[[9-(2thienylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate as aresidue (compound 10);

ethyl4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate(compound 11);

ethyl4-[[9-(5-methyl-2-furanyl)methyl]-9H-purin-8-yl]amino]-1-piperidine-carboxylateas a residue (compound 12);

ethyl4-[[9-(2-pyrazinylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylateas a residue (compound 13);

ethyl 4-[(9-methyl-9H-purin-8-yl)amino]-1-piperidinecarboxylate; mp.169.6° C. (compound 14);

ethyl4-[[9-[(4-methoxyphenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinecarboxylate;mp. 168.1° C. (compound 15); and

N-[1-(phenylmethyl)-4-piperidinyl]-9H-purin-8-amine; mp. 276.1° C.(compound 16).

Example 16

A mixture of 15.7 parts of ethyl4-[[[[4-(cyclopropylamino)-5-pyrimidinyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate,20 parts of mercury(II) oxide, 40 parts of ethanol and 135 parts ofN,N-dimethylacetamide was stirred overnight at 80° C. The reactionmixture was filtered over diatomaceous earth while hot. The filtrate waspoured into water and the product was extracted with dichloromethane.The organic layer was dried, filtered and evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 2.2 parts (14.1%) of ethyl4-[(9-cyclopropyl-9H-purin-8-yl)amino]-1-piperidinecarboxylate; mp.177.0° C. (compound 17).

In a similar manner there was also prepared: ethyl4-[[9-(4-thiazolylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate(compound 18).

Example 17

A mixture of 13 parts of methylcis-4-[[[[4-[[(4-fluorophenyl)methyl]amino]-5-pyrimidinyl]amino]thioxomethyl]amino]-3-methyl-1-piperidinecarboxylate,13 parts of mercury(II) oxide, 0.1 parts of sulfur and 160 parts ofmethanol, saturated with ammonia was stirred for 0.5 hours at refluxtemperature. The reaction mixture was filtered over diatomaceous earthwhile hot and the filtrate was evaporated. The residue was poured intowater and the product was extracted with trichloromethane. The extractwas washed with water, dried, filtered and evaporated. The residue wassolidified in 1,1'-oxybisethane. The product was filtered off and dried,yielding 7 parts (58.5%) of methylcis-4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-3-methyl-1-piperidinecarboxylate;mp. 152.2° C. (compound 19).

In a similar manner there were also prepared:

7-[(4-fluorophenyl)methyl]-N-[1-(phenylmethyl)-4-piperidinyl]-7H-purin-8-amine;mp. 251.1° C. (compound 20). methyl(cis+trans)-4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-3-methyl-1-piperidinecarboxylate(compound 21);

In a similar manner there are also prepared: ethyl4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]methylamino]-1-piperidinecarboxylate(compound 22); and ethyl4-[[9-[(2,4-dimethylphenyl)methyl)methyl]-9H-purin-8-yl]amino]-1-piperidinecarboxylate(compound 23).

Example 18

A mixture of 88.8 parts of ethyl4-[[[(4-amino-6-hydroxy-5-pyrimidinyl)[(4-fluorophenyl)methyl]amino]thioxomethyl]amino]-1-piperidinecarboxylate,88 parts of mercury(II) oxide, 0.1 parts of sulfur and 1200 parts ofethanol was stirred overnight at reflux temperature. The reactionmixture was filtered over diatomaceous earth while hot and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (95:5 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom ethyl acetate. The product was filtered off and dried, yielding50.7 parts (66.1% ) of ethyl4-[[(7-amino-1-[(4-fluorophenyl)methyl]oxazolo[5,4-d]-pyrimidin-2(1H)-yliden]amino]-1-piperidinecarboxylate;mp. 174.6° C. (compound 24).

A mixture of 50.7 parts of ethyl4-[[7-amino-1-[(4-fluorophenyl)methyl]oxazolo[5,4-d]pyrimidin-2(1H)-yliden]amino]-1-piperidinecarboxylateand 3050 parts of phosphoryl chloride was stirred for 90 minutes atreflux temperature. The reaction mixture was evaporated. The residue waspoured into ice water. The whole was treated with ammonium hydroxide.The product was extracted with 4-methyl-2-pentanone. The extract waswashed with water, dried, filtered and evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from acetonitrile. The productwas filtered off and dried, yielding 21.6 parts (41.5%) of ethyl4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]amino-1-piperidinecarboxylate;mp. 126.6° C. (compound 25).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

1-[(4-fluorophenyl)methyl]-2,3-dihydro-2-[[1-(phenylmethyl)-4-piperidinyl]imino]oxazolo[5,4-d]-pyrimidine-4-amine;mp. 178.5° C. (compound 26); and

6-chloro-7-[(4-fluorophenyl)methyl[-N-[1-(phenylmethyl)-4-piperidinyl]-7H-purin-8-amine;mp. 248.6° C. (compound 27).

Example 19

A mixture of 16 parts of6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-7H-purine,4.65 parts of ethyl carbonochloridate and 180 parts of methylbenzene wasstirred for 2 hours at reflux temperature. After cooling, the reactionmixture was treated with ammonium hydroxide and the product wasextracted with methylbenzene. The extract was washed with water, dried,filtered and evaporated, yielding 18.7 parts (100%) of ethyl4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]methyl]-1-piperidinecarboxylateas a residue (compound 28).

In a similar manner there was also prepared:

ethyl4-[[9-[(4-fluorophenyl)methyl]-6-methyl-9H-purin-8-yl]methyl]-1-piperidinecarboxylate(compound 29); and

ethyl4-[[6-chloro-9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]methyl]-1-piperidinecarboxylateas a residue (compound 30).

Example 20

A mixture of 24.8 parts of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidineand 300 parts of acetic acid, saturated with hydrogen bromide wasstirred overnight at room temperature. After evaporation, the residuewas taken up in water. The whole was treated with a sodium hydroxidesolution and extracted with dichloromethane. The extract was acidifiedwith a hydrochloric acid solution and extracted with water. The aqueouslayer was treated with a sodium hydroxide solution and the product wasextracted with dichloromethane. The extract was washed with water,dried, filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, (95:5 by volume)→trichloromethane and methanol, saturated withammonia, (90:10 by volume) as eluents. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized fromacetonitrile. The product was filtered off and dried, yielding 3.0 parts(17.4%) of 9-[(4-fluorophenyl)methyl[-8-(4-piperidinylthio)-9H-purine;mp. 113.5° C. (compound 31).

In a similar manner there is also prepared:9-[(4-fluorophenyl)methyl[-8-(4-piperidinylsulfonyl)-9H-purine (compound32).

Example 21

A mixture of 60.5 parts of ethyl4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-1-piperidinecarboxylate, 90parts of potassium hydroxide, 800 parts of 2-propanol and 20 parts ofwater was stirred for 48 hours at reflux temperature. The reactionmixture was evaporated. The reaction mixture was poured into water whilestirring. The product was filtered off and dried, yielding a firstfraction of 36.2 parts of9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine hemihydrate. Theaqueous phase was extracted with dichloromethane. The organic layer wasdried, filtered and evaporated. The oily residue was stirred inacetonitrile and 2,2'-oxybispropane. The product was filtered off anddried, yielding a second fraction of 5.6 parts of9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine. Total yield 41.8parts (86%) of 9-(2-furanylmethyl)-N-(4-piperidinyl)-9H-purin-8-aminehemihydrate; mp. 164.1° C. (compound 33).

Following the same procedure and using equivalent amounts of theappropriate starting materials, there were also prepared:

9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-aminedihydrochloride; mp. 275.0° C. (compound 34);

N-(4-piperidinyl)-9-(2-thienylmethyl)-9H-purin-8-amine; mp. 189.6° C.(compound 35);

N-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine; mp. 194.8° C.(compound 36);

9-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine; mp.165.1° C. (compound 37);

N-(4-piperidinyl)-9-(2-pyrazinylmethyl)-9H-purin-8-amine as a residue(compound 38); and

9-[(4-methoxyphenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-aminehemihydrate; mp. 144.1° C. (compound 39).

In a similar manner there is also prepared:

9[(2,4-dimethylphenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine(compound 40).

Example 22

A mixture of 7.5 parts of ethyl4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8yl]amino]-1-piperidinecarboxylateand 150 parts of a hydrobromic acid solution 48% in water was stirredovernight at 80° C. The reaction mixture was evaporated. The residue wasstirred in 2-propanone. The product was filtered off and dried, yielding8.5 parts (100%) of7-[(4-fluorophenyl)methyl]-8-(4-piperidinylamino)-7H-purin-6-oldihydrobromide as a residue (compound 41).

In a similar manner there were also prepared:9-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-9H-purin-6-oldihydrobromide as a residue (compound 42); and

7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-oldihydrobromide; mp. 277.8° C. (compound 43).

Example 23

A mixture of 10.5 parts of ethyl4-[(9-methyl-9H-purin-8-yl)amino]-1-piperidinecarboxylate and 300 partsof a hydrobromic acid solution 48% in water was stirred for 6 hours at80° C. After evaporation, the residue was boiled in methanol. Thereaction mixture was cooled and the precipitated product was filteredoff, boiled in methanol again and yielded, after filtration and drying,7.7 parts (56.6%) of 9-methyl-N-(4-piperidinyl)-9H-purin-8-aminedihydrobromide; mp. 298.3° C. (compound 44).

In a similar manner there were also prepared:

cis-9-[(4-fluorophenyl)methyl]-N-(3-methyl-4-piperidinyl)-9H-purin-8-aminedihydrobromide (compound 45);

9-(phenylmethyl)-N-(4-piperidinyl)-9H-purin-8-amine dihydrobromide; mp.270.9° C. (compound 46);

(cis+trans)-9-[(4-fluorophenyl)methyl]-N-(3-methyl-4-piperidinyl)-9H-purin-8-aminedihydrobromide (compound 47);

9-[(4-fluorophenyl)methyl]-6-methyl-8-(4-piperidinyl)methyl)-9H-purineas a residue (compound 48);

9cyclopropyl-N-(4-piperidinyl)-9H-purin-8-amine; mp. 140.6° C. (compound49); and

N-(4-piperidinyl)-9-(4-thiazolylmethyl)-9H-purin-8-amine; mp. 208.4° C.(compound 50).

In a similar manner there is also prepared:9-[4-fluorophenyl)methyl]-N-methyl-N-(4-piperidinyl)-9H-purin-8-amine(compound 51).

Example 24

A mixture of 17.6 parts of9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purineand 200 parts of methanol was hydrogenated at normal pressure and atroom temperature with 2 pairs of palladium-on-charcoal catalyst 10%.After the calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated. The residue was taken upin water. The product was extracted with trichloromethane. The extractwas dried, filtered and evaporated. The residue was converted into theethanedioate salt in ethanol. The salt was filtered off and dried,yielding 8.1 parts (38.1%) of9-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-9H-purineethanedioate(1:2); mp. 163.9° C. (compound 52).

In a similar manner there were also prepared:

7-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)]-7H-purin-8-amine as aresidue (compound 53); and

9-[(4-fluorophenyl)methyl]-6-methoxy-8-(4-piperidinylmethyl)-9H-purine(compound 54).

Example 25

A mixture of 15 parts of6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-7H-purine,5 parts of calcium oxide and 200 parts off methanol was hydrogenated atnormal pressure and at room temperature with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was taken up in water. The product wasextracted with dichloromethane. The extract was dried, filtered andevaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (95:5→85:15 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated, yielding 5.8 parts (54%) of7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purine as aresidue (compound 55).

Example 26

A mixture of 16.25 parts of9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purineand 200 parts of methanol was hydrogenated at normal pressure and at 50°C. with b 3 parts of palladium-on-charcoal catalyst 10% and 6 parts ofRaney-nickel catalyst. After the calculated amount of hydrogen was takenup, the catalyst was filtered off and the filtrate was evaporated. Theresidue was taken up in trichloromethane and water was added. Theproduct was extracted with trichloromethane. The extract was washed withwater, dried, filtered and evaporated. The residue was stirred in1,1'-oxybisethane. The precipitated product was filtered off and dried,yielding 10.5 parts (82.2%) of9-[(4-fluorophenyl)methyl]-8-(4-piperidinyloxy)-9H-purine; mp. 79.3° C.(compound 56).

Example 27

A mixture of 3.2 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol4-methylbenzenesulfonate(ester), 5 parts of9-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-9H-purin-6-oldihydrobromide, 3 parts of sodium carbonate and 45 parts ofN,N-dimethylacetamide was stirred overnight at 70° C. After cooling, thereaction mixture was filtered over diatomaceous earth and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (90:10 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedtwice: first from acetonitrile and then from ethanol. The product wasfiltered off and dried, yielding 0.8 parts (16.3%) of8-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-9-[(4-fluorophenyl)methyl]-9H-purin-6-ol;mp. 200.7° C. (compound 57).

In a similar manner there was also prepared:

8-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]amino]-7-[(4-fluorophenyl)methyl]-7H-purin-6-ol;mp. 257.5° C. (compound 58).

Example 28

A mixture of 3.2 parts of 2,3-dihydro-1,4-benzodioxin-2-methanol4-methylbenzenesulfonate (ester), 4.5 parts of7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-oldihydrobromide, 4 parts of sodium carbonate and 45 parts ofN,N-dimethylformamide was stirred overnight at 70° C. After cooling, thereaction mixture was filtered over diatomaceous earth and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (95:5 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 1.5parts (34%) of8-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-7-[(4-fluorophenyl)methyl]-7H-purin-6-ol;mp. 175.2° C. (compound 59).

In a similar manner there were also prepared:

N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-9-(2-furanyl-methyl)-9H-purin-8-aminedihydrochloride dihydrate; mp. 174.4° C. (compound 60); and

N-[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]-9-[(5-methyl-2-furanyl)methyl]-9H-purin-8-amine;mp. 200.8° C. (compound 61).

Example 29

A mixture of 1.9 parts of 1-(2-chloroethyl)-4-methoxybenzene, 5 parts of7-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-7H-purin-6-oldihydrobromide, 4 parts of sodium carbonate and 45 parts ofN,N-dimethylacetamide was stirred overnight at 70° C. After cooling, thereaction mixture was filtered over diatomaceous earth and the filtratewas evaporated. The residue was purified by column chromatography oversilica gel using a mixture of trichloromethane and methanol, saturatedwith ammonia, (95:5 by volume) as eluent. The pure fractions werecollected and the eluent was evaporated. The residue was crystallizedfrom acetonitrile. The product was filtered off and dried, yielding 2.2parts (46%) of7-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-7H-purin-6-ol;mp. 122.2° C. (compound 62).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR44##                                                                                                                  isom.                                                                            mp.                          No.                                                                              L            R.sup.2                                                                          B  R.sup.1     A.sup.1A.sup.2A.sup.3A.sup.4                                                              form                                                                             °C.                   __________________________________________________________________________    63 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  CH.sub.2                                                                         4-FC.sub.6 H.sub.4CH.sub.2                                                                NCNC(OH)    -- 197.0                        64 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  O  4-FC.sub.6 H.sub.4CH.sub.2                                                                NCNC        -- 120.0                        65 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 CH.sub.3                                                                         NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                NCNC        cis                                                                              160.5                        66 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  NH CH.sub.3    NCNC        -- 136.5                        67 4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                        H  NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                CNCN        -- 216.0                        68 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  NH cyclopropyl-                                                                              NCNC        -- 166.1                        69 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  NH 4-thiazolyl-CH.sub. 2                                                                     NCNC        -- 152.2                        70 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  NH 4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                       NCNC        -- 167.8                        71 4-CH.sub.3 OC.sub.6 H.sub.4C.sub.2 H.sub.5                                                 H  S  4-FC.sub.6 H.sub.4CH.sub.2                                                                NCNC        -- 102.0                        __________________________________________________________________________

In a similar manner there are also prepared:

9-[(4-fluorophenyl)methyl]-8-[[1-[2-(2-methoxyphenyl)ethyl]-4-piperidinyl]methyl]-9H-purine(compound 72).

9-[(4-fluorophenyl)methyl]-N-methyl-N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-9H-purin-8-amine(compound 73).

Example 30

A mixture of 2 parts of 1-(2-chloroethyl)-4-methoxybenzene, 3.1 parts ofN-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts ofsodium carbonate and 45 parts of N,N-dimethylformamide was stirredovernight at 70° C. The reaction mixture was poured into water. Theproduct was extracted with dichloromethane. The extract was dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 2.2 parts (50%) ofN-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-9-(2-pyridinylmethyl)-9H-purin-8-amine;mp. 144.5° C. (compound 74).

    __________________________________________________________________________     ##STR45##                                                                    No.                                                                              R.sup.1      A.sup.1A.sup.2A.sup.3A.sup.4                                                               Base or salt form                                                                         mp. °C.                       __________________________________________________________________________    75 4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC         base        170.6                                76 2-furanyl-CH.sub.2                                                                         NCNC         base        140.6                                77 2-thienyl-CH.sub.2                                                                         NCNC         hemihydrate 135.9                                78 4-FC.sub.6 H.sub.4CH.sub.2                                                                 CNCN         base        194.9                                79 5-CH.sub.3 -2-furanyl-CH.sub.2                                                             NCNC         base        164.9                                80 4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC         (E)-2-butenedioate (2:3)                                                                  156.2                                81 4-FC.sub.6 H.sub.4CH.sub.2                                                                 CNCN         base        139.1                                82 4-FC.sub.6 H.sub.4CH.sub.2                                                                 C(OH)NCN     monohydrate 222.4                                83 C.sub.6 H.sub.5CH.sub.2                                                                    NCNC         base        161.5                                84 4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC(CH.sub.3)                                                                             (E)-2-butenedioate (1:2)                                                                  148.0                                __________________________________________________________________________

In a similar manner there was also prepared: ethyl[2-[4-[[9-(2-thienylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]carbamateas a residue (compound 85).

In a similar manner there is also prepared:

9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]sulfonyl]-9H-purine(E)-2-butenedioate(1:2) (compound 86).

Example 31

A mixture of 1.45 parts of3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 2 parts ofN-(4-piperidinyl)-9-(2-pyrazinylmethyl)-9H-purin-8-amine, 1 part ofsodium carbonate and 45 parts of N,N-dimethylacetamide was stirred andheated overnight at 90° C. The reaction mixture was poured into water.The product was extracted with trichloromethane. The extract was dried,filtered and evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 0.9 parts (31.6%) of2-methyl-3-[2-[4-[[9-(2-pyrazinylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]-ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one;mp. 180.1° C. (compound 87).

    __________________________________________________________________________     ##STR46##                                                                    No.                                                                              B  R.sup.1      R.sup.2                                                                           A.sup.1A.sup.2A.sup.3A.sup.4                                                               Base or salt form                                                                         mp. °C.                __________________________________________________________________________    88 NH 2-furanyl-CH.sub.2                                                                         H   NCNC         H.sub.2 O   176.6                         89 NH 2-thienyl-CH.sub.2                                                                         H   NCNC         base        194.3                         90 NH 2-pyridinyl-CH.sub.2                                                                       H   NCNC         base        201.3                         91 NH 5-CH.sub.3 -2-furanyl-CH.sub.2                                                             H   NCNC         base        208.1                         92 CH.sub.2                                                                         4-FC.sub.6 H.sub.4 CH.sub.2                                                                H   NCNC         (E)-2-butenedioate (2:5)                                                                  180.0                         93 NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   CNCN         base        211.5                         94 CH.sub.2                                                                         4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   CNCN         3HCl.2H.sub.2 O                                                                           217.5                         95 CH.sub.2                                                                         4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   NCNC(OH)     1/2 H.sub.2 O                                                                             196.5                         96 NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   C(OH)NCN     H.sub.2 O   201.9                         97 CH.sub.2                                                                         4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   C(OH)NCN     base        210.1                         98 O  4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   NCNC         base        152.4                         99 NH CH.sub.3     H   NCNC         1/2 H.sub.2 O                                                                             213.0                         100                                                                              NH C.sub.6 H.sub.5CH.sub.2                                                                    H   NCNC         base        239.2                         101                                                                              NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                 3-CH.sub.3                                                                        NCNC         base/cis + trans                                                                          212.5                         102                                                                              NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                 H   NCNC(CH.sub.3)                                                                             base        148.9                         103                                                                              NH 4-thiazolyl-CH.sub.2                                                                       H   NCNC         base        222.0                         __________________________________________________________________________

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR47##                                                                                                    Base or                                                                            mp.                                      No.                                                                              B   R.sup.1     A.sup.1A.sup.2A.sup.3A.sup.4                                                               salt form                                                                          °C.                               __________________________________________________________________________    104                                                                              NH  2-furanyl-CH.sub.2                                                                        NCNC         base 181.6                                    105                                                                              NH  2-thienyl-CH.sub.2                                                                        NCNC         H.sub.2 O                                                                          168.2                                    106                                                                              NH  2-pyridinyl-CH.sub.2                                                                      NCNC         H.sub.2 O                                                                          164.7                                    107                                                                              NH  5-CH.sub.3 -2-furanyl-CH.sub.2                                                            NCNC         base 173.4                                    __________________________________________________________________________

In a similar manner there were also prepared:

3-[2-[4-[[9-[(4-fluorophenyl)methyl]-6-hydroxy-9H-purin-8-yl]-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one;mp. 171.1° C. (compound 108);

1-[3-[4-[[9-[(4-fluorophenyl)methyl]-6-methoxy-9H-purin-8-yl]methyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one(E)-2-butenedioate(2:3); mp. 179.9° C. (compound 109);

9-[(4-fluorophenyl)methyl]-N-[1-[2-(4-morpholinyl)ethyl]-4-piperidinyl]-9H-purin-8-amine;mp. 176.8° C. (compound 110);

7-methyl-6-[2-[4-[[9-(2-thienylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-5H-thiazolo[3,2-a]pyrimidin-5-onehemihydrate; mp. 104.5° C. (compound 111);

1-ethyl-4-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-1,4-dihydro-5H-tetrazol-5-one;mp. 160.3° C. (compound 112); and

3-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-2,4-(1H,3H)quinazolinedione;mp. 241.0° C. (compound 113).

Example 32

A mixture of 1.8 parts of1-(3-chloropropyl)-1,3-dihydro-2H-benzimidazol-2-one, 2.7 parts of9-[(4-fluorophenyl)methyl]-8-(4-piperidinylmethyl)-9H-purine, 1 part ofsodium carbonate and 45 parts of N,N-dimethylformamide was stirred andheated overnight at 70° C. After cooling, the reaction mixture waspoured into water. The product was extracted with trichloromethane. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the (E)-2-butenedioate saltin ethanol. The salt was filtered off and dried, yielding 2.85 parts(45.9%) of1-[3-[4-[[9-[(4-fluorophenyl)methyl]-9H-purine-8-yl]methyl]-1-piperidinyl]-propyl]-1,3-dihydro-2H-benzimidazol-2-one(E)-2-butenedioate(1:2); mp. 186.2° C. (compound 114).

In a similar manner there were also prepared:

1-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-puri-8-yl]amino]-1-piperidinyl]ethyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 242.4° C. (compound 115);

1-[3-[4-[[9-[(4-fluorophenyl)methyl]-6-hydroxy-9H-purin-8-yl]methyl]-1-piperidinyl]propyl]-1,3-dihydro-2H-benzimidazol-2-one;mp. 245.8° C. (compound 116).

In a similar manner there are also prepared:

3,7-dimethyl-6-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8yl]methyl]-1-piperidinyl]ethyl]-5H-thiazolo[3,2-a]pyrimidin-5-one(compound 117);

3-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]thio]-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound 118);

3-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]sulfonyl]-1-piperidinyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one(compound 119).

Example 33

A mixture of 1.2 parts of bromo-1-propene, 3.26 parts of9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1.5 partsof sodium hydrogen carbonate and 40 parts of ethanol was stirred for 1hour at reflux temperature. The reaction mixture was filtered overdiatomaceous earth while hot and the filtrate was evaporated. Theresidue was taken up in water and the product was extracted with4-methyl-2-pentanone. The extract was dried, filtered and evaporated.The residue was purified by column chromatography over silica gel usinga mixture of trichloromethane and methanol, saturated with ammonia,(95:5 by volume) as eluent. The pure fractions were collected and theeluent was evaporated. The residue was crystallized from acetonitrile.The product was filtered off and dried, yielding 0.8 parts (22%) of9-[(4-fluorophenyl)methyl]-N-[1-(2-propenyl)-4-piperidinyl)-9H-purin-8-amine;mp. 144.8° C. (compound 120).

In a similar manner there was also prepared:

4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-N-(1-methylethyl)-1-piperidinepropanamide(E)-2-butenedioate(1:2); mp. 202.5° C. (compound 121).

Example 34

A mixture of 3.46 parts ofN-(dihydro-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminiumbromide, 3.1 parts ofN-(4-piperidinyl)-9-(2-pyridinylmethyl)-9H-purin-8-amine, 1.5 parts ofsodium carbonate and 45 parts of N,N-dimethylacetamide was stirredovernight at 80° C. after cooling, the reaction mixture was poured intowater and the product was extracted with 4-methyl-2-pentanone. Theextract was dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from acetonitrile. The productwas filtered off and dried, yielding 4.1 parts (71%) ofN,N-dimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide;mp. 191.6° C. (compound 122).

    __________________________________________________________________________     ##STR48##                                                                                                   Base or  mp.                                   No.                                                                              B  R.sup.1      A.sup.1A.sup.2A.sup.3A.sup.4                                                              salt form                                                                              °C.                            __________________________________________________________________________    123                                                                              NH 5-CH.sub.3 -2-furanyl-CH.sub.2                                                             NCNC        1/2 H.sub.2 O                                                                          87.5                                  124                                                                              NH C.sub.6 H.sub.5CH.sub.2                                                                    NCNC        base     204.2                                 125                                                                              NH 2-furanyl-CH.sub.2                                                                         NCNC        base     201.5                                 126                                                                              CH.sub.2                                                                         4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC(OH)    base     139.2                                 127                                                                              NH 2-thienyl-CH.sub.2                                                                         NCNC        base     197.7                                 128                                                                              NH 4-FC.sub.6 H.sub.4CH.sub.2                                                                 NCNC        2HCl     208.6                                 129                                                                              NH cyclopropyl  NCNC        (E)-2-butendioate                                                                      172                                                                  (2:5)                                          130                                                                              NH 4-CH.sub.3 OC.sub.6 H.sub.4CH.sub.2                                                        NCNC        (E)-2-butendioate                                                                      132.3                                                                (2:5)                                          __________________________________________________________________________

In a similar manner there were also prepared:

N,N,γ-trimethyl-α,α-diphenyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinebutanamide;mp. 143.0° C. (compound 131);

4-[(9-methyl-9H-purin-8-yl)amino]-N,N-dimethyl-α,α-diphenyl-1-piperidinebutanamide(compound 132);

γ,N,N-trimethyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]methyl-.alpha.,α-diphenyl-1-piperidinebutanamide(compound 133);

4-[[9-(2-furanylmethyl)-9H-purin-8-yl]amino]-γ,N,N-trimethyl-α,α-diphenyl-1-piperidinebutanamide(compound 134); and

γ,N,N-trimethyl-4-[[9-[(5-methyl-2-furanyl)methyl]-9H-purin-8-yl]amino]-.alpha.,α-diphenyl-1-piperidinebutanamide(compound 135).

In a similar manner there are also prepared:

β,N,N-trimethyl-4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-α,α-diphenyl-1-piperidinebutanamide(compound 136); and

4-[[9-[(4-fluorophenyl)methyl]-N,N-dimethyl-α,α-diphenyl-9H-purin-8-yl]oxy]-1-piperidinebutanamide(compound 137).

Example 35

A mixture of 4.9 parts of9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine, 1 part ofa solution of thiophene in methanol 4%, 120 parts off methanol and 8parts of 2-propanone was hydrogenated at normal pressure and at roomtemperature with 2 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen was taken up, the catalyst wasfiltered off and the filtrate was evaporated. The residue was purifiedby column chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile, yielding 1.5 parts (27.2%) of9-[(4-fluorophenyl)methyl]-N-[1-(1-methylethyl)-4-piperidinyl]-9H-purin-8-amine;mp. 185.6° C. (compound 138).

Example 36

A mixture of 3 parts of poly(oxymethylene), 5 parts of7-[(4-fluorophenyl)methyl]-8-(4-piperidinylamino)-7H-purin-6-oldihydrobromide, 1 part of a solution of thiophene in methanol 4%, 5parts of potassium acetate and 120 parts of methanol was hydrogenated atnormal pressure and at room temperature with 2 parts ofpalladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen was taken up, the catalyst was filtered off and the filtratewas evaporated. The residue was taken up in water and the whole wastreated with sodium carbonate. The product was extracted withdichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol, saturated with ammonia, (95:5by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was crystallized from acetonitrile. Theproduct was filtered off and dried, yielding 2 parts (56%) of7-[(4-fluorophenyl)methyl]-8-[(1-methyl-4-piperidinyl)amino]-7H-purin-6-ol; mp. 255.6° C. (compound 139).

In a similar manner there was also prepared:

9-[(4-fluorophenyl)methyl]-8-[(1-methyl-4-piperidinyl)methyl]-9H-purin-6-olmp. 219.0° C. (compound 140).

Example 37

A mixture of 1.93 parts of 2-ethenylpyridine, 5 parts of9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine and 80parts of 1-butanol was stirred and refluxed overnight. The reactionmixture was evaporated. The residue was purified by columnchromatography over silica gel using first a mixture of trichloromethaneand methanol (95:5 by volume) and then a mixture of trichloromethane andmethanol, saturated with ammonia (95:5 by volume) as eluent. The purefractions were collected and the eluent was evaporated. The residue wascrystallized from acetonitrile, yielding 1 part (15%) of9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9H-purin-8-amine;mp. 172.3° C. (compound 141).

In a similar manner there were also prepared:

9-(2-furanylmethyl)-N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9H-purin-8-amine;mp. 144.5° C. (compound 142);

N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9-(2-thienylmethyl)-9H-purin-8-amine;mp. 152.7° C. (compound 143);

N-[1-[2-(2-pyridinyl)ethyl]-4-piperidinyl]-9-(2-pyridinylmethyl)-9H-purin-8-amine;mp. 163.8° C. (compound 144); and

9-[(5-methyl-2-furanyl)methyl]-N-[1-[2-(2-pyridinyl)ethyl]-4a-piperidinyl]-9H-purin-8-amine;mp. 163.2° C. (compound 145).

Example 38

During 30 minutes, gaseous oxirane was bubbled through a stirred mixtureof 5 parts of9-[(4-fluorophenyl)methyl]-N-(4-piperidinyl)-9H-purin-8-amine and 80parts of methanol at room temperature. After stirring for 3 hours atroom temperature, the reaction mixture was evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was crystallized from acetonitrile, yielding 2.2parts (40%) of

4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidine-ethanol;mp. 158.7° C. (compound 146).

Example 39

A mixture of 3.22 parts of 2-chloroacetonitrile, 16 parts of9-[(4-fluorophenyl)methyl]-N-4-piperidinyl)-9H-purin-8-amine, 12.7 partsof sodium carbonate and 225 parts of N,N-dimethylformamide was stirredfor 6 hours at room temperature. The reaction mixture was poured ontowater. The product was extracted twice with trichloromethane. Thecombined extracts were dried, filtered and evaporated. The residue wascrystallized from acetonitrile. The precipitate was filtered off and thefiltrate was evaporated, yielding 16 parts of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrileas a residue (compound 147).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR49##                                                                    No.                                                                              L       R.sup.1     B  A.sup.1A.sup.2A.sup.3A.sup.4                                                                mp. °C.                        __________________________________________________________________________    148                                                                              NCCH.sub.2                                                                            2-furanyl-CH.sub.2                                                                        NH NCNC          --                                    149                                                                              NC(CH.sub.2).sub.4                                                                    2-furanyl-CH.sub.2                                                                        NH NCNC          --                                    150                                                                              NCCH.sub.2                                                                            2-pyridinyl-CH.sub.2                                                                      NH NCNC          --                                    151                                                                              NCCH.sub.2                                                                            5-CH.sub.3 -2-furanyl-CH.sub.2                                                            NH NCNC          --                                    152                                                                              NCCH.sub.2                                                                            4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub.2                                                                         NCNC(OCH.sub.3)                                                                             --                                    153                                                                              NCCH.sub.2                                                                            4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub. 2                                                                        NCNC(OH)      --                                    154                                                                              NCCH.sub.2                                                                            4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub.2                                                                         NCNC          --                                    __________________________________________________________________________

Example 40

A mixture of 18.2 parts of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidineacetonitrileand 240 parts of methanol saturated with ammonia was hydrogenated atnormal pressure and at a temperature below 20° C. with 3 parts ofRaney-nickel catalyst. After the calculated amount of hydrogen was takenup, the catalyst was filtered off and the filtrate was evaporated. Theresidue was crystallized from acetonitrile. The product was filtered offand dried, yielding 16 parts (87.5%) ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine;mp. 146.1° C. (compound 155).

In a similar manner there were also prepared:

    __________________________________________________________________________     ##STR50##                                                                    No.                                                                              L        R.sup.1     B  A.sup.1A.sup.2A.sup.3A.sup.4                                                                mp. °C.                       __________________________________________________________________________    156                                                                              NH.sub.2(CH.sub.2).sub.2                                                               2-furanyl-CH.sub.2                                                                        NH NCNC          --                                   157                                                                              NH.sub.2(CH.sub.2).sub.5                                                               2-furanyl-CH.sub.2                                                                        NH NCNC          --                                   158                                                                              NH.sub.2(CH.sub.2).sub.2                                                               2-pyridinyl-CH.sub.2                                                                      NH NCNC          --                                   159                                                                              NH.sub.2(CH.sub.2).sub.2                                                               5-CH.sub.3 -2-furanyl-CH.sub.2                                                            NH NCNC          --                                   160                                                                              NH.sub.2(CH.sub.2).sub.2                                                               4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub.2                                                                         NCNC(OCH.sub.3)                                                                             --                                   161                                                                              NH.sub.2(CH.sub.2).sub.2                                                               4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub.2                                                                         NCNC(OH)      --                                   162                                                                              NH.sub.2(CH.sub.2).sub.2                                                               4-FC.sub.6 H.sub.4CH.sub.2                                                                CH.sub.2                                                                         NCNC          --                                   __________________________________________________________________________

Example 41

A mixture of 10 parts of ethyl[2-[4-[[9-(2-thienylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]carbamate,10 parts of potassium hydroxide and 240 parts of 2-propanol was stirredovernight at reflux temperature. The reaction mixture was evaporated.Water was added. After stirring, the product was filtered off and dried,yielding 3.6 parts (56%) ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-(2-thienylmethyl)-9H-purin-8-amine(compound 163).

Example 42

A mixture of 1.7 parts of 2-chloropyrimidine, 5.5 parts ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine,1.5 parts of sodium hydrogen carbonate and 160 parts of ethanol wasstirred and refluxed for 20 hours. The reaction mixture was evaporated.The residue was purified by column chromatography over silica gel usinga mixture of trichloromethane and methanol (95:5 by volume) as eluent.The pure fractions were collected and the eluent was evaporated. Theresidue was crystallized from acetonitrile, yielding 4.5 parts (67%) of9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-pyrimidinylamino)ethyl]-4-piperidinyl]-9H-purin-8-amine;mp. 164.1° C. (compound 164).

    __________________________________________________________________________     ##STR51##                                                                                                    base or                                                                              mp.                                    No.                                                                              R.sup.1     B  A.sup.1A.sup.2A.sup.3A.sup.4                                                                salt form                                                                            °C.                             __________________________________________________________________________    165                                                                              2-furanyl-CH.sub.2                                                                        NH NCNC          base   135.5                                  166                                                                              2-pyridinyl-CH.sub.2                                                                      NH NCNC          base   140.1                                  167                                                                              2-thienyl-CH.sub.2                                                                        NH NCNC          base   157.2                                  168                                                                              5-CH.sub.3 -2-furanyl-CH.sub.2                                                            NH NCNC          base   174.1                                  169                                                                              4-FC.sub.6 H.sub.4 CH.sub.2                                                               CH.sub.2                                                                         NCNC(OCH.sub.3)                                                                             base   138.1                                  170                                                                              4-FC.sub.6 H.sub.4 CH.sub.2                                                               CH.sub.2                                                                         NCNC(OH)      base   212.9                                  171                                                                              4-FC.sub.6 H.sub.4 CH.sub.2                                                               CH.sub.2                                                                         NCNC          ethanedioate                                                                         102.1                                                                  (1:3)                                         __________________________________________________________________________

Example 43

A mixture of 3.3 parts of 2-bromothiazole, 5.55 parts ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine,2.12 parts of sodium carbonate and 18 parts of N,N-dimethylacetamide wasstirred and heated for 20 hours at 130° C. After cooling, the reactionmixture was poured onto water and the product was extracted with4-methyl-2-pentanone. The extract was dried, filtered and evaporated.The residue was purified by column chromatography over silica gel usinga mixture of trichloromethane, methanol and methanol saturated withammonia, (90:5:5 by volume) as eluent. The pure fractions were collectedand the eluent was evaporated. The residue was crystallized fromacetonitrile. The product was filtered off and dried in high vacuo at100° C., yielding 1.8 parts (26.5%) of9-[(4-fluorophenyl)methyl]-N-[1-[2-(2-thiazolylamino)ethyl)-4-piperidinyl]-9H-purin-8-amine;mp. 165.4° C. (compound 172).

In a similar manner there was also prepared:

9-(2-furanylmethyl)-N-[1-[4-[(2-thiazolyl)amino]pentyl]-4-piperidinyl]-9H-purin-8-amine;mp. 167.4° C. (compound 173).

In a similar manner there is also prepared:

N²-[2-[4-[[9-(2-pyridinylmethyl)-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-1,3,4-thiadiazole-2,5-diamine(compound 174).

Example 44

A mixture of 1.1 parts of 3-furancarboxylic acid, 2.55 parts of2-chloro-1-methylpyridinium iodide, 2 parts of N,N-diethylethanamine and360 parts of dichloromethane was stirred for 2 hours at roomtemperature. A solution of 3.7 parts ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-aminein dichloromethane was added and stirring was continued overnight atroom temperature. The reaction mixture was washed with water. Theseparated organic layer was dried, filtered and evaporated. The residuewas purified by column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the (E)-2-butenedioate saltin a mixture of ethanol, 2-propanol and acetonitrile. The salt wasfiltered off and dried, yielding 2 parts (29%) ofN-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-3-furancarboxamide(E)-2-butenedioate(1:2); mp. 132.2° C. (compound 175).

In a similar manner there were also prepared:

N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-2-thiophenecarboxamide(E)-2-butenedioate (1:2) monohydrate; mp. 135.7° C. (compound 176); and

N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-2-thiazolecarboxamide(E)-2-butenedioate (1:2); mp. 184.0° C. (compound 177).

Example 45

A mixture of 1.4 parts of 2H-3,1-benzoxazine-2,4-(1H)-dione, 3.7 partsofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amineand 45 parts of N,N-dimethylformamide was stirred for 4 hours at 70° C.After cooling, the reaction mixture was poured into water and theproduct was extracted with 4-methyl-2-pentanone. The extract was washedwith water, dried, filtered and evaporated. The residue was purified bycolumn chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (95:5 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the (E)-2-butenedioate saltin ethanol. The salt was filtered off and dried, yielding 4.3 parts(50%) of2-amino-N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]benzamide(E)-2-butenedioate(2:5): mp. 164° C. (compound 178).

Example 46

A mixture of 0.7 parts of isothiocyanatomethane, 3.7 parts ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amineand 90 parts of tetrahydrofuran was stirred for 4 hours at roomtemperature. After evaporation, the residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95:5 by volume) as eluent. The firstfraction was collected and the eluent was evaporated. The residue wascrystallized from acetonitrile. The product was filtered off and dried,yielding 1.3 parts (29%) ofN-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]-N'-methylthiourea;mp. 205.5° C. (compound 179).

In a smaller manner there is also prepared:

N-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]methyl]-1-piperidinyl]ethyl]-N'-ethylurea;(compound 180).

Example 47

To a stirred and cooled (-10° C.) mixture of 5.6 parts ofN,N'-methanetetraylbis[cyclohexanamine], 13.9 parts of carbon disulfideand 90 parts of tetrahydrofuran were added portionwise 10 parts ofN-[1-(2-aminoethyl)-4-piperidinyl]-9-[(4-fluorophenyl)methyl]-9H-purin-8-amine.Upon completion, the temperature was allowed to rise to room temperatureand the reaction mixture was evaporated, yielding 16 parts of9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine(compound 181).

A mixture of 2.95 parts of 3,4-pyridinediamine, 16 parts of9-[(4-fluorophenyl)methyl]-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-9H-purin-8-amine,and 90 parts of tetrahydrofuran was stirred and refluxed overnight. Thereaction mixture was evaporated. The residue was purified by columnchromatography over silica gel using a mixture of trichloromethane andmethanol, saturated with ammonia, (95/5 by volume) as eluent. The purefractions were collected and the eluent was evaporated, yielding 10.5parts ofN-(4-amino-3-pyridinyl)-N'-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]thiourea(compound 182).

A mixture of 10.5 parts ofN-(4-amino-3-pyridinyl)-N'-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]-amino]-1-piperidinyl]ethyl]thiourea,6 parts of mercury(II) oxide, 1 part of sulfur and 120 parts of ethanolwas stirred and refluxed overnight. The reaction mixture was filteredover Hyflo® while hot. The filtrate was evaporated. The residue waspurified by column chromatography over silica gel using a mixture oftrichloromethane and methanol, saturated with ammonia, (90:10 by volume)as eluent. The pure fractions were collected and the eluent wasevaporated. The residue was converted into the (E)-2-butenedioate saltin ethanole. The salt was filtered off and dried, yielding 4 parts (17%)of9-[(4-fluorophenyl)methyl]-N-[1-[2-[(1H-imidazo[4,5-c]pyridin-2-yl)amino]ethyl]-4-piperidinyl]-9H-purin-8-amine(E)-2-butenedioate(1:3) monohydrate; mp. 191.0° C. (compound 183).

Example 48

To a previously prepared sodium methoxide solution, starting from 25parts of sodium in 400 parts of methanol, were added 49.4 parts of6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine.After stirring for 8 hours at reflux temperature, the reaction mixturewas cooled and 1000 parts of water were added. The precipitated productwas filtered off and dried, yielding 34.5 parts (70.4%) of9-[(4-fluorophenyl)methyl]-6-methoxy-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-9H-purine(compound 184).

Example 49

A mixture of 3 parts of6-chloro-9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]-methyl]-9H-purineand 50 parts of a hydrochloric acid solution 1N was stirred and refluxedfor 1.5 hours. After cooling, the mixture was made alkaline withammonium hydroxide. The product was extracted with trichloromethane. Theextract was washed with water, dried, filtered and evaporated. Theresidue was crystallized from a mixture of acetonitrile and ethanol. Theproduct was filtered off and dried, yielding 1.5 parts (52%) of9-[(4-fluorophenyl)methyl]-1,9-dihydro-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-6H-purin-6-one;mp. 197.0° C. (compound 185).

Example 50

A mixture of 2.7 parts of9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-methyl]-9H-purin-6-oland 75 parts of a hydrobromic acid solution 48% in water was stirred for4 hours at 80° C. After evaporation, the residue was taken up in waterand treated with sodium carbonate. The product was extracted withtrichloromethane. The extract was dried, filtered and evaporated. Theresidue was purified by column chromatography over silica gel using amixture of trichloromethane and methanol, saturated with ammonia, (90:10by volume) as eluent. The pure fractions were collected and the eluentwas evaporated. The residue was crystallized from ethanol andacetonitrile. The product was filtered off and dried, yielding 1 part(38.6%) of9-[(4-fluorophenyl)methyl]-8-[[1-[2-(4-hydroxyphenyl)ethyl]-4-piperidinyl]methyl]-9H-purin-6-ol;mp. 215.7° C. (compound 186).

In a similar manner there was also prepared:

4-[[4-[[7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]amino]-1-piperidinyl]methyl]phenol;mp. 228.1° C. (compound 187).

In a similar manner there is also prepared:

2-[2-[4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]amino]-1-piperidinyl]ethyl]phenol(compound 188).

Example 51

To a stirred solution of 7.2 parts of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]thio]-1-[(4-methylphenyl)sulfonyl]piperidinein 195 parts of dichloromethane is added dropwise a solution of 7 partsof 3-chlorobenzenecarboperoxoic acid in 65 parts of dichloromethane.Upon completion, stirring is continued for 2 hours at room temperature.The whole is washed with a sodium carbonate solution and twice withwater, dried, filtered and evaporated. The residue is crystallized fromacetonitrile. The product is filtered off and dried, yielding 3 parts(40%) of4-[[9-[(4-fluorophenyl)methyl]-9H-purin-8-yl]sulfonyl]-1-[(4-methylphenyl)sulfonyl]piperidine;(compound 189).

C. Pharmacological Examples

The useful antihistaminic properties of the compounds of formula (I) aredemonstrated in the following test procedure.

Example 52 Protection of rats from compound 48/80-induced lethality.

Compound 48/80, a mixture of oligomers obtained by condensation of4-methoxy-N-methylbenzeneethanamine and formaldehyde has been describedas a potent histamine releasing agent (Int. Arch. Allergy, 13, 336(1958)). The protection from compound 48/80-induced lethal circulatorycollapse appears to be a simple way of evaluating quantitatively theantihistaminic activity of test compounds. Male rats of an inbred Wistarstrain, weighing 240-260 g were used in the experiment. After overnightstarvation the rats were transferred to conditioned laboratories(temp.=21±1° C., relative humidity=65±5%). The rats were treatedsubcutaneously or orally with a test compound or with the solvent (NaClsolution, 0.9%). One hour after treatment there was injectedintravenously compound 48/80, freshly dissolved in water, at a dose of0.5 mg/kg (0.2 ml/100 g of body weight). In control experiments, wherein250 solvent-treated animals were injected with the standard dose ofcompound 48/80, not more than 2.8% of the animals survived after 4hours. Survival after 4 hours is therefore considered to be a safecriterion of a protective effect of drug administration.

The ED₅₀ -values of the compounds of formula (I) are listed in Table 1.Said ED₅₀ -values are the values in mg/kg body weight at which thetested compounds protect 50% of the tested animals against compound48/80-induced lethality.

                  TABLE 1                                                         ______________________________________                                                      compound 48/80                                                                lethality test in                                                             rats-ED.sub.50  in mg/kg                                        Compound No.  body weight                                                     ______________________________________                                        60            0.08                                                            61            0.01                                                            62            0.04                                                            64            0.08                                                            74            0.01                                                            75            0.08                                                            76            0.02                                                            77            0.02                                                            78            0.04                                                            79            0.04                                                            80            0.04                                                            81            0.04                                                            83            0.08                                                            87            0.08                                                            88            0.02                                                            89            0.08                                                            100           0.02                                                            104           0.04                                                            106           0.08                                                            107           0.02                                                            114           0.04                                                            115           0.08                                                            141           0.01                                                            142           0.02                                                            143           0.02                                                            144           0.04                                                            145           0.01                                                            165           0.02                                                            167           0.08                                                            168           0.02                                                            169           0.08                                                            171           0.08                                                            172           0.04                                                            173           0.08                                                            183           0.04                                                            ______________________________________                                    

D) Composition Examples

The following formulations exemplify typical pharmaceutical compositionsin dosage unit form suitable for systemic administration to animal andhuman subjects in accordance with the instant invention.

"Active ingredient" (A.I.) as used throughout these examples relates toa compound of formula (I) or a pharmaceutically acceptable acid additionsalt thereof.

Example 53: ORAL DROPS

500 Grams of the A.I. was dissolved in 0.5 liters of 2-hydroxypropanoicacid and 1.5 liters of the polyethylene glycol at 60°-80° C. Aftercooling to 30°-40° C. there were added 35 liters of polyethylene glycoland the mixture was stirred well. Then there was added a solution of1750 grams of sodium saccharin in 2.5 liters of purified water and whilestirring there were added 2.5 liters of cocoa flavor and polyethyleneglycol q.s. to a volume of 50 liters, providing an oral drop solutioncomprising 10 milligrams of the A.I. per milliliter. The resultingsolution was filled into suitable containers.

Example 54: ORAL SOLUTION

9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl4-hydroxybenzoate were dissolved in 4 liters of boiling purified water.In 3 liters of this solution were dissolved first 10 grams of2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. Thelatter solution was combined with the remaining part of the formersolution and 12 liters 1,2,3-propanetriol and 3 liters off sorbitol 70%solution were added thereto. 40 Grams of sodium saccharin were dissolvedin 0.5 liters of water and 2 millimeters of raspberry and 2 millilitersof gooseberry essence were added. The latter solution was combined withthe former, water was added q.s. to a volume of 20 liters providing anoral solution comprising 20 milligrams of the active ingredient perteaspoonful (5 milliliters). The resulting solution was filled insuitable containers.

Example 55: CAPSULES

20 Grams of the A.I., 6 grams sodium lauryl sulfate, 56 grams starch, 56grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 gramsmagnesium stearate were vigorously stirred together. The resultingmixture was subsequently filled into 1000 suitable hardened gelatingcapsules, comprising each 20 milligrams of the active ingredient.

Example 56: FILM-COATED TABLETS Preparation of tablet core

A mixture of 100 grams of the A.I., 570 grams lactose and 200 gramsstarch was mixed well and thereafter humidified with a solution of 5grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone(Kollidon-K 90®) in about 200 milliliters of water. The wet powdermixture was sieved, dried and sieved again. Then there was added 100grams microcrystalline cellulose (Avicel®) and 15 grams hydrogenatedvegetable oil (Sterotex®). The whole was mixed well and compressed intotablets, giving 10,000 tablets, each containing 10 milligrams of theactive ingredient.

Coating

To a solution of 10 grams methyl cellulose (Methocel 60 HG®) in 75milliliters of denaturated ethanol there was added a solution of 5 gramsof ethyl cellulose (Ethocel 22 cps®) in 150 milliliters ofdichloromethane. Then there were added 75 milliliters of dichloromethaneand 2.5 milliliters 1,2,3-propanetriol. 10 Grams of polyethylene glycolwas molten and dissolved in 75 milliliters of dichloromethane. Thelatter solution was added to the former and then there were added 2.5grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30milliliters of concentrated colour suspension (Opaspray K-1-2109®) andthe whole was homogenated. The tablet cores were coated with the thusobtained mixture in a coating apparatus.

Example 57: INJECTABLE SOLUTION

1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl4-hydroxybenzoate were dissolved in about 0.5 liters of boiling waterfor injection. After cooling to about 50° C. there were added whilestirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams ofthe A.I.

The solution was cooled to room temperature and supplemented with waterfor injection q.s. ad 1 liter volume, giving a solution of 4 milligramsA.I. per milliliters. The solution was sterilized by filtration (U.S.P.XVII p. 811) and filled in sterile containers.

Example 58: SUPPOSITORIES

3 Grams A.I. was dissolved in a solution of 3 grams2,3-dihydroxybutanedioic acid in 25 milliliters polyethylene glycol 400.12 Grams surfactant (SPAN®) and triglycerides (Witepsol 555®) q.s. ad300 grams were molten together. The latter mixture was mixed well withthe former solution. The thus obtained mixture was poured into moulds ata temperature of 37°-38° C. to form 100 suppositories each containing 30milligrams of the active ingredient.

What we claim is:
 1. A compound of the formula: ##STR52## apharmaceutically acceptable acid addition salt or a possiblestereochemically isomeric form thereof, wherein:--A¹ ═A² --A³ ═A⁴ --represents a bivalent radical of the formula:

    --N═CH--N═CH--                                     (a-1),

or

    --CH═N--CH═N--                                     (a-2),

wherein one or two hydrogen atoms in said radicals (a-1) or (a-2) may,each independently from each other, be replaced by halo, C₁₋₆ alkyl,C₁₋₆ alkyloxy, trifluoromethyl, or hydroxy;R¹ represents a memberselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₆cycloalkyl, Ar¹, and C₁₋₆ alkyl substituted with one or two Ar¹radicals; R² represents a member selected from the group consisting ofhydrogen and C₁₋₆ alkyl; B represents NR; said R being a member selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyloxy)carbonyl, and Ar² -C₁₋₆ alkyl; andL represents a radical of the formula:

    Ar.sup.1 --T--C.sub.s H.sub.2s --                          (b-1);

whereins represents an integer of from 1 to 6 inclusive; and Trepresents O, S, NR³, or a direct bond, wherein R³ represents hydrogen,C₁₋₆ alkyl, or Ar² --C₁₋₆ alkyl; wherein in the foregoing Ar¹ representsa member selected from the group consisting of phenyl, substitutedphenyl, pyridinyl, mono- and di(C₁₋₆ alkyloxy)pyridinyl, furanyl,furanyl substituted with C₁₋₆ alkyl, and thiazolyl; said substitutedphenyl being phenyl substituted with up to 3 substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino; and whereinAr² represents a member selected from the group consisting of phenyl andsubstituted phenyl; said substituted phenyl being phenyl optionallysubstituted with up to three substituents each independently selectedfrom the group consisting of halo, hydroxy, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy.
 2. An anti-allergic composition comprising suitablepharmaceutical carriers and as active ingredient an anti-allergic amountof a compound of the formula: ##STR53## a pharmaceutically acceptableacid addition salt or a possible stereochemically isomeric form thereof,wherein:--A¹ ═A² --A³ ═A⁴ -- represents a bivalent radical of theformula:

    --N═CH--N═CH--                                     (a-1),

or

    --CH═N--CH═N--                                     (a-2),

wherein one or two hydrogen atoms in said radicals (a-1) or (a-2) may,each independently from each other, be replaced by halo, C₁₋₆ alkyl,C₁₋₆ alkyloxy, trifluoromethyl, or hydroxy;R¹ represents a memberselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₆cycloalkyl, Ar¹, and C₁₋₆ alkyl substituted with one or two Ar¹radicals; R² represents a member selected from the group consisting ofhydrogen and C₁₋₆ alkyl; B represents NR; said R being a member selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyloxy)carbonyl, and Ar² --C₁₋₆ alkyl; andL represents a radical of the formula:

    Ar.sup.1 --T--C.sub.s H.sub.2s --                          (b-1);

whereins represents an integer of from 1 to 6 inclusive; and Trepresents O, S, NR³, or a direct bond, wherein R³ represents hydrogen,C₁₋₆ alkyl, or Ar² --C₁₋₆ alkyl; wherein in the foregoing Ar¹ representsa member selected from the group consisting of phenyl, substitutedphenyl, pyridinyl, mono- and di(C₁₋₆ alkyloxy)pyridinyl, furanyl,furanyl substituted with C₁₋₆ alkyl, and thiazolyl; said substitutedphenyl being phenyl substituted with up to 3 substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino; and whereinAr² represents a member selected from the group consisting of phenyl andsubstituted phenyl; said substituted phenyl being phenyl optionallysubstituted with up to three substituents each independently selectedfrom the group consisting of halo, hydroxy, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy.
 3. A method of treating allergic diseases in warm-bloodedanimals suffering from the same, which method comprises the systemicadministration to warm-blooded animals of an effective anti-allergicamount of a compound of the formula: ##STR54## a pharmaceuticallyacceptable acid addition salt or a possible stereochemically isomericform thereof, wherein:--A¹ ═A² --A³ ═A⁴ -- represents a bivalent radicalof the formula:

    --N═CH--N═CH--                                     (a-1),

or

    --CH═N--CH═N--                                     (a-2),

wherein one or two hydrogen atoms in said radicals (a-1) or (a-2) may,each independently from each other, be replaced by halo, C₁₋₆ alkyl,C₁₋₆ alkyloxy, trifluoromethyl, or hydroxy;R¹ represents a memberselected from the group consisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₆cycloalkyl, Ar¹, and C₁₋₆ alkyl substituted with one or two Ar¹radicals; R² represents a member selected from the group consisting ofhydrogen and C₁₋₆ alkyl; B represents NR; said R being a member selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,(C₁₋₆ alkyl)carbonyl, (C₁₋₆ alkyloxy)carbonyl, and Ar² --C₁₋₆ alkyl; andL represents a radical of the formula:

    Ar.sup.1 --T--C.sub.2 H.sub.2s --                          (b-1);

whereins represents an integer of from 1 to 6 inclusive; and Trepresents O, S, NR³, or a direct bond, wherein R³ represents hydrogen,C₁₋₆ alkyl, or Ar² --C₁₋₆ alkyl; wherein in the foregoing Ar¹ representsa member selected from the group consisting of phenyl, substitutedphenyl, pyridinyl, mono- and di(C₁₋₆ alkyloxy)pyridinyl, furanyl,furanyl substituted with C₁₋₆ alkyl, and thiazolyl; said substitutedphenyl being phenyl substituted with up to 3 substituents eachindependently selected from the group consisting of halo, hydroxy,nitro, cyano, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkyloxy, C₁₋₆alkylthio, mercapto, amino, mono- and di(C₁₋₆ alkyl)amino; and whereinAr² represents a member selected from the group consisting of phenyl andsubstituted phenyl; said substituted phenyl being phenyl optionallysubstituted with up to three substituents each independently selectedfrom the group consisting of halo, hydroxy, trifluoromethyl, C₁₋₆ alkyl,C₁₋₆ alkyloxy.
 4. A compound according to claim 1 wherein R¹ representsC₁₋₆ alkyl substituted with one Ar¹ radical.
 5. An anti-allergiccomposition according to claim 2 wherein R¹ represents C₁₋₆ alkylsubstituted with one Ar¹ radical.
 6. A method according to claim 3wherein R¹ represents C₁₋₆ alkyl substituted with one Ar¹ radical.